Ppar agonists

ABSTRACT

Provided herein are compounds and compositions useful in increasing PPARδ activity. The compounds and compositions provided herein are useful for the treatment of PPARδ related diseases (e.g., muscular diseases, vascular disease, demyelinating disease, and metabolic diseases).

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of International ApplicationNo. PCT/US2014/033088, filed on Apr. 4, 2014, which claims the benefitof the earlier filing dates of U.S. Provisional Application No.61/809,182, filed on Apr. 5, 2013, and U.S. Provisional Application No.61/812,434, filed on Apr. 16, 2013, each of which is incorporated hereinby reference in their entirety.

ACKNOWLEDGMENT OF GOVERNMENT SUPPORT

This invention was made with government support under DK057978-32awarded by the National Institutes of Health. The United Statesgovernment has certain rights in the invention.

FIELD

This application concerns agonists of peroxisome proliferator-activatedreceptors (PPAR), particularly PPAR delta (PPARδ), and methods for theiruse, such as to treat or prevent one or more PPARδ-related diseases.

JOINT RESEARCH AGREEMENT

The Salk Institute for Biological Studies and Mitokyne, now known asMitobridge, Inc., (Boston, Mass.) are parties to a joint researchagreement for the purposes of performing experimental, developmental, orresearch work in the field of the claimed invention.

BACKGROUND

Skeletal muscle is a mechanically and energetically active organ,supporting vital processes such as respiration and locomotion, and is amajor site of glucose and lipid metabolism. Therefore, maintainingproper muscle mass and function is critical. Muscle incurs damage due toa variety of insults such as use, disuse, aging and pathology. Whileskeletal muscle does not undergo rapid turn-over under normalconditions, upon being damaged, it is capable of executing a robustregenerative response through mobilization of its resident progenitorcells, the satellite cells (Moss F P, Leblond C P, Anat Rec 170:421-436(1970); Schultz E, Gibson M C, Champion T, J Exp Zool 206(3):451-6(1978); Snow M H, Cell Tissue Res 186(3):535-40 (1978)). Theself-renewal and differentiation capacity of the satellite cells havealluded to the archetypic “stemness,” but their fate seems largelycommitted (Sinanan A C M, Buxton P G, Lewis M P, Bio Cell 98:203-214(2006); Beauchamp J R et al., J Cell Biol 151:1221-1234 (2000); StarkeyJ D et al., J Histochem Cytochem 59(1):33-46 (2011)). In an adult,satellite cells comprise less than 5% of total nuclei on a myofiber;nevertheless, based on their proliferation kinetics and capacity, thisis sufficient to regenerate an entire muscle (Schmalbruch H, HellhammerU, Anat Rec 189:169-176 (1977); Kelly A M, Dev Bio 65(1): 1-10 (1978);Gibson M C, Schultz E, Anat Rec 202(3):329-337 (1982); Bischoff R inMyology, Vol 1, eds Engel A G, Franzini-Armstrong C (McGraw-Hill, Inc.,New York), (1994); Zammit P S et al., Exp Cell Res 281:39-49 (2002)).

Upon injury, skeletal muscle responds to damage in three distinct butoverlapping phases: degeneration, regeneration and finally remodeling(Charge S B P, Rudnicki M A, Physiol Rev 84:209-238 (2004)). Immediatelyfollowing the injury, inflammatory cells are recruited to the injurysite to promote degeneration of the damaged tissue through necrosis andphagocytosis (Tidball J G, Am J Physiol Regul Integr Comp Physio288:R345-353 (2005); McLennan I S, J Anat 188:17-28 (1996);Pimorady-Esfahani A, Grounds M D, McMenamin P G, Muscle Nerve 20:158-166(1997); Vierck J et al., Cell Bio Int 24:263-272 (2000); Arnold L etal., J Exp Med 204(5):1057-1069 (2007)). The subsequent regenerativephase is characterized by mobilization of satellite cells, whereby theprogenitor cells proliferate, differentiate and fuse to each other or tothe existing fibers to regenerate the muscle (Zammit P S in Skeletalmuscle repair and regeneration, eds Schiaffino S, Partridge T (Springer,Dordrecht (2008)). Finally, the contractile proteins are reassembled andfunction is restored during the remodeling phase.

SUMMARY

Provided herein, inter alia, are compounds and compositions comprisingsuch compounds that are useful for increasing PPAR activity,particularly PPARδ activity. Also disclosed are methods of using thedisclosed compositions for treating or preventing PPARδ related diseases(e.g., muscular diseases, demyelinating disease, vascular disease, andmetabolic diseases).

Certain disclosed embodiments concern compounds having a formula

With reference to this formula, ring A may be selected from acycloalkylene, heterocycloalkylene, arylene or heteroarylene; ring B isselected from an aryl, heteroaryl, cycloalkyl, heterocycloalkyl,cycloalkylene, heterocycloalkylene, arylene or heteroarylene; each R²independently is selected from deuterium, halogen, aryl, heteroaryl,aliphatic, heteroaliphatic, cycloaliphatic, NO₂, OH, amino, amide,aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, SO₃H, or acyl;each R²² independently is selected from deuterium, halogen, aryl,heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO₂, OH, amino,amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, SO₃H, oracyl; n is from 0 to 5; m is from 0 to 4; X is O, NR³⁰, sulfonyl, or S;R³⁰ is selected from H or aliphatic, aryl, or cycloaliphatic; L⁵ isselected from a bond, aliphatic, heteroaliphatic, arylene,heteroarylene, cycloalkylene, heterocycloalkylene or -L³N(L⁴R³)L³-; L²is selected from a bond, aliphatic, heteroaliphatic, arylene,heteroarylene, cycloalkylene, heterocycloalkylene or —CR²³R²⁴—; R²³ andR²⁴ are each independently selected from H, deuterium, halogen,aliphatic, alkyl, —C(O)OR²⁵ or —C(O)NR²⁵R²⁶; R²⁵ and R²⁶ are eachindependently hydrogen or aliphatic, alkyl; Z is selected from R¹L¹C(O)—or a carboxyl bioisostere; L¹ is a bond or —NR³⁰—; R¹ is hydrogen,aliphatic, —OR^(1A), —NR^(1A)R^(1B), —C(O)R^(1A), —S(O)₂R^(1A),—C(O)OR^(1A), —S(O)₂NR^(1A)R^(1B) or —C(O)NR^(1A)R^(1B); R^(1A), R^(1B)are each independently hydrogen or aliphatic, alkyl; L³ is selected froma bond, aliphatic, —C(O)—, alkylC(O)—, aliphaticC(O)—, —C(O)aliphatic,—C(O)alkyl-, or sulfonyl; L⁴ is selected from a bond, aliphatic,heteroaliphatic, arylene, heteroarylene, cycloalkylene,heterocycloalkylene or —CR²³R²⁴—; R³ is selected from —OH, —OR^(3A),—NR^(3A)R^(3B), —C(O)R^(3A), —S(O)₂R^(3A), —C(O)OR^(3A),—S(O)₂NR^(3A)R^(3B), —C(O)NR^(3A)R^(3B), aliphatic, heteroaliphatic,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or R³ can be joined withan atom of ring B to form a fused ring system or may be joined with anatom of L³ to form a heterocyclic ring system; and R^(3A), R^(3B), areeach independently hydrogen or aliphatic, alkyl. In certain disclosedembodiment, if L⁵ is —CH₂N(L⁴R³)C(O)—, L⁴R³ is n-propyl or isopropyl,ring A is phenyl, and n is 1 then R² is not 4-bromo or4-benzo[d][1,3]dioxole; if L⁵ is —CH₂CH₂N(L⁴R³)C(O)NH—, X is S, and L⁴R³is an unbranched aliphatic or alkyl chain, then L⁴R³ is a C₁-C₆unbranched aliphatic or alkyl chain; if L⁵ is —CH₂CH₂N(L⁴R³)C(O)NH—, Xis S, and L⁴ is an unbranched aliphatic or alkyl chain, then R³ is not acyclohexyl; if L⁵ is —CH₂N(L⁴R³)C(O)—, L⁴R³ is isopropyl, ring A andring B are both phenyl, and n is 1 then the —XL²Z moiety is ortho orpara to L⁵, or L⁵ forms a fused ring with ring A. Furthermore, compoundsaccording to this formula are not selected from:4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}aceticacid;{4-[({2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}aceticacid;2-((4-(2-(3-(2,4-difluorophenyl)-1-heptylureido)ethyl)phenyl)thio)-2-methylpropanoicacid;2-((4-(2-(3-cyclohexyl-1-(4-cyclohexylbutyl)ureido)ethyl)phenyl)thio)-2-methylpropanoicacid;(S)-2-((2-(methoxycarbonyl)phenyl)amino)-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoicacid;2-((4-(2-(1-(4-cyclohexylbutyl)-3-(4-methoxyphenyl)ureido)ethyl)phenyl)thio)-2-methylpropanoicacid;2-((4-(2-(1-(4-cyclohexylbutyl)-3-(3-methoxyphenyl)ureido)ethyl)phenyl)thio)-2-methylpropanoicacid; ethyl 6-(2-((4-bromo-N-propylbenzamido)methyl)phenoxy)hexanoate;ethyl 6-(4-((4-bromo-N-propylbenzamido)methyl)phenoxy)hexanoate; ethyl6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoate;6-(4-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoate;6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoicacid;6-(4-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoicacid; ethyl6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate;ethyl6-(4-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate;6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid; or6-(4-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid. In certain embodiments, ring A is selected from aC₃-C₅cycloalkylene, C₂-C₅heterocycloalkylene, C₆-C₁₀arylene orC₁-C₁₀heteroarylene, with particular examples having ring A beingselected from phenyl, pyridine, cyclopentane, cyclohexane, pyrazole,thiophene or isothiazole. In certain embodiments, ring B is selectedfrom C₃-C₈cycloalkylene, C₂-C₅heterocycloalkylene, C₆-C₁₀arylene orC₁-C₁₀heteroarylene. In particular examples, ring B is selected fromphenyl, pyridine, thiophene, thiazole, pyrazole, oxazole, isoxazole,benzo[b]furan, indazole, piperidine, cyclohexane, piperidin-2-one,piperazine-2,5-dione or quinazolin-4(3H)-one.

Certain disclosed compounds include carboxyl biostere functionalities,such as

each independently is selected from N, CH₂ or CO; X⁸ is selected from O,S or NMe; and X⁹ is selected from O, N, NH, S, CH or CH₂.

More particular embodiments concern compounds having one more of thefollowing formulas:

wherein X¹ is selected from carbon, nitrogen, or N-oxide;

wherein X¹ is selected from carbon, nitrogen, or N-oxide;

wherein Z¹ is selected from carbon, oxygen, sulfur, or NR³⁰, and each Yindependently is selected from carbon or nitrogen;

wherein Z¹ is selected from carbon, oxygen, sulfur, or NR³⁰, and each Yindependently is selected from carbon or nitrogen;

wherein X² is selected from a bond, carbon, oxygen, sulfur, or NR³⁰;

wherein each X³ independently is selected from nitrogen, carbon, NR³⁰,or oxo, and each Y independently is selected from carbon or NR³⁰;

With reference to any of the prior compound formulas, in certainembodiments: R³ may be selected from aliphatic, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl; L², L³ and L⁴ eachindependently is a bond or alkylene; L⁴R³ is isopropyl; R² is furan-2-ylor furan-3-yl; L² may be selected from

or halogenated, versions thereof, particularly fluorinated compounds;R²² is selected from Cl, F, I, Br, alkyloxy, haloalkyloxy,cycloalkyloxy, cyano, haloalkyl, CD₃, OCD₃, aliphatic, alkyl, alkenyl,alkynyl, amino, heterocyclic, aryl, cycloaliphatic or heteroaryl,particularly Br, F, methyl, trifluoromethyl, cyano, methoxy, cyclopropylor azetidine; R² is selected from Cl, F, I, Br, alkyloxy, haloalkyloxy,cycloalkyloxy, cyano, haloalkyl, CD₃, OCD₃, aliphatic, alkyl, alkenyl,alkynyl, amino, heterocyclic, aryl, cycloaliphatic or heteroaryl; n isfrom 2 to 4; two adjacent R² groups may form a fused ring system withring B, with particular compounds having R² selected from bromo, fluoro,methyl, trifluoromethyl, methoxy, trifluoromethoxy, dimethylamino,acetyl, methanesulfonyl, cyano, cyclopropoxy, phenyl, furan-2-yl,furan-3-yl, thiophen-2-yl, thiophen-3-yl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-n-butylphenyl, 4-n-propylphenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl,2-ethylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl,3,5-dimethylphenyl, 3-pyridyl, 4-pyridyl, naphthalen-1-yl,naphthalen-2-yl, (1,1′-biphenyl)-2-yl, pyrrolidin-1-yl,3-(furan-3-yl)phenyl,

Pharmaceutical compositions also are disclosed. Particular embodimentscomprise a pharmaceutically acceptable excipient and one or moredisclosed compounds.

A method of activating PPARδ also is disclosed. For certain embodiments,the method comprises contacting a PPARδ protein with an effective amountof one or more disclosed compounds, or a pharmaceutical compositioncomprising one or more disclosed compounds, thereby activating the PPARδprotein. The PPARδ protein may be present in a subject, and contactingcomprises administering the one or more compounds to the subject.Activating the PPARδ protein within the subject may increase or maintainmuscle mass or muscle tone in the subject.

Another embodiment comprises treating a PPARδ-related disease orcondition in a subject by administering to the subject in need thereof atherapeutically effective amount of one or more disclosed compounds, ora pharmaceutical composition comprising the compound(s). In certainembodiments, the PPARδ-related disease is a vascular disease; a musculardisease, such as a muscular dystrophy disease, with particular examplesincluding Duchenne muscular dystrophy, Becker muscular dystrophy,limb-girdle muscular dystrophy, congenital muscular dystrophy,facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy,oculopharyngeal muscular dystrophy, distal muscular dystrophy, orEmery-Dreifuss muscular dystrophydemyelinating disease; a demyelinatingdisease, such as multiple sclerosis, Charcot-Marie-Tooth disease,Pelizaeus-Merzbacher disease, encephalomyelitis, neuromyelitis optica,adrenoleukodystrophy, or Guillian-Barre syndrome; a muscle structuredisorder, such as Bethlem myopathy, central core disease, congenitalfiber type disproportion, distal muscular dystrophy (MD), Duchenne &Becker MD, Emery-Dreifuss MD, facioscapulohumeral MD, hyaline bodymyopathy, limb-girdle MD, a muscle sodium channel disorder, myotonicchondrodystrophy, myotonic dystrophy, myotubular myopathy, nemaline bodydisease, oculopharyngeal MD, or stress urinary incontinence; a neuronalactivation disorder, such as amyotrophic lateral sclerosis,Charcot-Marie-Tooth disease, Guillain-Barre syndrome, Lambert-Eatonsyndrome, multiple sclerosis, myasthenia gravis, nerve lesion,peripheral neuropathy, spinal muscular atrophy, tardy ulnar nerve palsy,or toxic myoneural disorder; a muscle fatigue disorder, such as chronicfatigue syndrome, diabetes type I or II, glycogen storage disease,fibromyalgia, Friedreich's ataxia, intermittent claudication, lipidstorage myopathy, MELAS, mucopolysaccharidosis, Pompe disease, orthyrotoxic myopathy; the muscle mass disorder is cachexia, cartilagedegeneration, cerebral palsy, compartment syndrome, critical illnessmyopathy, inclusion body myositis, muscular atrophy (disuse),sarcopenia, steroid myopathy, or systemic lupus erythematosus; amitochondrial disease, such as Alpers's Disease, CPEO-Chronicprogressive external ophthalmoplegia, Kearns-Sayra Syndrome (KSS), LeberHereditary Optic Neuropathy (LHON), MELAS-Mitochondrial myopathy,encephalomyopathy, lactic acidosis, and stroke-like episodes,MERRF-Myoclonic epilepsy and ragged-red fiber disease, NARP-neurogenicmuscle weakness, ataxia, and retinitis pigmentosa, or Pearson Syndrome;a beta oxidation disease, such as systemic carnitine transporter,carnitine palmitoyltransferase (CPT) II deficiency, very long-chainacyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzymedeficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency,short-chain acyl-CoA dehydrogenase (SCAD) deficiency orriboflavin-responsive disorders of β-oxidation (RR-MADD); a metabolicdisease, such as hyperlipidemia, dyslipidemia, hyperchlolesterolemia,hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemiaand/or HLD non-cholesterolemia, VLDL hyperproteinemia,dyslipoproteinemia, apolipoprotein A-I hypoproteinemia, atherosclerosis,disease of arterial sclerosis, disease of cardiovascular systems,cerebrovascular disease, peripheral circulatory disease, metabolicsyndrome, syndrome X, obesity, diabetes, type I or type II,hyperglycemia, insulin resistance, impaired glucose tolerance,hyperinsulinism, diabetic complication, cardiac insufficiency, cardiacinfarction, cardiomyopathy, hypertension, Non-alcoholic fatty liverdisease (NAFLD), Nonalcoholic steatohepatitis (NASH), thrombus,Alzheimer disease, neurodegenerative disease, demyelinating disease,multiple sclerosis, adrenal leukodystrophy, dermatitis, psoriasis, acne,skin aging, trichosis, inflammation, arthritis, asthma, hypersensitiveintestine syndrome, ulcerative colitis, Crohn's disease, orpancreatitis; a cancer, such as a cancer of the colon, large intestine,skin, breast, prostate, ovary, or lung; a vascular disease, such asperipheral vascular insufficiency, peripheral vascular disease,intermittent claudication, peripheral vascular disease (PVD), peripheralartery disease (PAD), peripheral artery occlusive disease (PAOD), orperipheral obliterative arteriopathy; an ocular vascular disease, suchas age-related macular degeneration (AMD), stargardt disease,hypertensive retinopathy, diabetic retinopathy, retinopathy, maculardegeneration, retinal haemorrhage, or glaucoma; or a muscular eyedisease, such as strabismus, progressive external ophthalmoplegia,esotropia, exotropia, a disorder of refraction and accommodation,hypermetropia, myopia, astigmatism, anisometropia, presbyopia, disordersof accommodation, or internal ophthalmoplegia.

For certain disclosed method embodiments, the subject is a sedentary orimmobilized subject. In other embodiments, the subject may be anexercising subject.

For disclosed embodiments, administering may comprise intraarticular,intravenous, intramuscular, intratumoral, intradermal, intraperitoneal,subcutaneous, oral, topical, intrathecal, inhalational, transdermal,rectal administration, or any combination thereof. The one or morecompounds are administered to the subject at an effective dose, such asa dose of from greater than 0 mg/kg, such as from about 1 mg/kg to about20 mg/kg, or from about 2 mg/kg to about 10 mg/kg, with certainembodiments being administered at a dose of from about 2 mg/kg to about5 mg/kg.

The foregoing and other objects and features of the disclosure willbecome more apparent from the following detailed description, whichproceeds with reference to the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B are bar graphs showing removery of damaged muscle fibersafter injury.

FIGS. 1C-1F show VP16-PPARδ transgenic animals exhibit acceleratedmuscle regeneration after acute injury. All error bars are SEM.

FIG. 1C provides two images of transverse sections of TA of WT and TGanimals, with damaged fibers stained by Evans Blue dye 5 days after theinjury.

FIG. 1D provides the proportion of stained area over the totalcross-sectional area (CSA) of TA (n=5; **P<0.01).

FIG. 1E provides quantification of Evans Blue stain at 12 hours afterinjury (n=3).

FIG. 1F provides quantification of Evans Blue stain at 36 hours afterinjury (n=3).

FIGS. 1G-1J illustrate VP16-PPARδ transgenic animals that exhibitaccelerated muscle regeneration after acute injury. All error bars areSEM. *P<0.05; **P<0.01; ***P<0.001; n.s.=not significant.

FIG. 1G provides H&E stained transverse sections of injured transversusabdominus muscle (TA) from wildtype (WT) and transgenic (TG) animals.Representative images are from 3, 5 and 7 days after injury.Arrows=regenerating fibers with centralized nuclei. Arrowheads=hollowedremains of basal lamina. Asterisks=uninjured fibers.

FIG. 1H illustrates the average number of regenerating fibers per field.

FIG. 1I illustrates the average CSA of regenerating myofiber (n=5 forday 5; n=11 for day 7).

FIG. 1J illustrates the average CSA of regenerating myofiber, 21 daysafter injury (n=5).

FIGS. 2A-E illustrate that PPARδ activation promotes a temporal shift ingene expression profile of the regenerative process. *P<0.05. All errorbars are SEM.

FIG. 2A provides a GO classification of injury specific upregulatedgenes in TG (n=3).

FIG. 2B shows the relative expression of regeneration markers in TG.

FIG. 2C is a graph of relative expression versus days post injury,illustrating post injury temporal gene expression profiles ofinflammatory marker CD68, measured by QPCR (n=5).

FIG. 2D is a graph of relative expression versus days post injury,illustrating post injury temporal gene expression profiles of a myogenicmarker MyoD by Q-PCR (n=5).

FIG. 2E is a bar graph showing the Myh8 mRNA level 5 days post injury(n>5).

FIGS. 3A-3G illustrate that PPARδ regulates FGF1a to promotemicro-vascularization. *P<0.05; **P<0.01. All error bars are SEM.

FIG. 3A provides immunofluorescence staining for CD31 on transversesections of uninjured TA from WT and TG animals.

FIG. 3B provides quantification of CD31 positive capillary number (n=4).

FIG. 3C illustrates the FGF1a mRNA level in TA of WT and TG by QPCR(n=5).

FIG. 3D provides a Western blot for FGF1.

FIG. 3E provides immunofluorescence staining for CD31 positivecapillaries on transverse sections of TA, 5 days after the injury (n=3).

FIG. 3F provides quantification for CD31 positive capillaries ontransverse sections of TA, 5 days after the injury (n=3).

FIG. 3G provides luciferase reporter assays of FGF1a promoterco-transfected with PPARδ with or without the ligand, GW501516.

FIG. 4A-4E illustrate that the skeletal muscle specific activation ofPPARδ increases the quiescent satellite cell pool. All error bars areSEM. *P<0.05; **P<0.01.

FIG. 4A provides digital images of isolated myofibers from lateralgastrocnemius of 8-week-old nestin reporter mice with or withoutVP16-PPARδ transgene.

FIG. 4B is a bar graph showing quantification of GFP+ satellite cellsper unit length of myofiber (n=3).

FIG. 4C is a bar graph showing the proportion of BrdU positive nuclei at0.5, 1 and 2 days after injury (n=5).

FIG. 4D is a bar graph showing VP16 mRNA levels in whole TA or satellitecells (SC) from WT and TG.

FIG. 4E is a bar graph showing PPARδ mRNA levels in whole TA orsatellite cells (SC) from WT and TG.

FIGS. 5A-5E illustrate that acute pharmacological activation of PPARδconfers regenerative advantage. *P<0.05; **P<0.01; ***P<0.001. All errorbars are SEM.

FIG. 5A is a series of bar graphs showing PPARδ target gene expressionin TA after 9 day treatment with either vehicle or GW501516 (n=6).

FIG. 5B provides digital images of transverse TA sections showing EvansBlue dye uptake 5 days after the injury.

FIG. 5C is a bar graph showing the proportions of stained area (n=5) inthe images of FIG. 5B.

FIG. 5D is a bar graph showing the percentage of BrdU positive nuclei 2days after injury (n=4).

FIG. 5E is a series of bar graphs showing TNFα and F480 levels 3 daysafter injury measured by QPCR (n=6).

FIGS. 6A-6E show VP16-PPARδ transgenic animals exhibit acceleratedmuscle regeneration after the acute injury. All error bars are SEM.

FIG. 6A shows serum creatine kinase levels in wildtype and VP16-PPARδtransgenic animals.

FIG. 6B shows transverse sections of TA of WT and TG animals. Stainingof damaged fibers by Evans Blue dye 5 days after the injury.

FIG. 6C shows proportion of stained area over the total CSA of TA (n=5;**P<0.01).

FIGS. 6D and 6E show quantification of Evans Blue stain at 12 and 36hours after injury (n=3).

FIG. 7A shows transverse sections of TA of WT and TG animals. Stainingof damaged fibers by Evans Blue 3 days after the injury.

FIG. 7B shows Injury dependent induction of PPARδ by QPCR (n=5).

FIG. 7C shows post injury temporal gene expression profiles ofinflammatory markers TNFα.

FIG. 7D shows induction of VEGFα in TA muscle, as measured by WesternBlot, in TG animals.

FIG. 7E shows quantification of TNFα Western Blot.

FIG. 8A provides up-regulated Notch pathway components in TG animals bymicroarray analysis (n=3).

FIG. 8B provides graphs of QPCR for gene expression of Notch pathwaycomponents in 2 months old WT or TG animals (n=5).

FIG. 8C provides graphs of QPCR for gene expression of Notch pathwaycomponents in 9 days treatment with GW501516 (n=6).

FIG. 8D provides graphs of QPCR for gene expression of Notch pathwaycomponents in 12 months old WT or TG animals (n=3).

FIGS. 9A-9E are graphs showing pharmacokinetic data for severalcompounds at 3 mg/kg i.v. or 10 mg/kg p.o.

FIGS. 10A and 10B are graphs showing relative quantities of free fattyacids in the brain (A) and liver (B) of AKO mice administered GW,compared to AKO mice not administered GW and wild-type mice.

FIG. 11A is a graph showing expression of mitochondrial fatty acidoxidation genes Cpt1a, Slc25a20, and Acadl in the livers of AKO miceadministered GW compared to AKO mice not administered GW.

FIG. 11B is a graph showing expression of mitochondrial fatty acidoxidation genes Cptlb, Slc25a20, and Acadl in the skeletal muscle of AKOmice administered GW compared to AKO mice not administered GW.

FIGS. 12A and 12B are graphs showing the relative quantities of totalfatty acids in the liver (A) and skeletal muscle (B) of AKO miceadministered GW compared to AKO mice not administered GW.

DETAILED DESCRIPTION I. Terms

The following explanations of terms and methods are provided to betterdescribe the present disclosure and to guide those of ordinary skill inthe art in the practice of the present disclosure. The singular forms“a,” “an,” and “the” refer to one or more than one, unless the contextclearly dictates otherwise. For example, the term “comprising a PPARδagonist” includes single or plural PPARδ agonists and is consideredequivalent to the phrase “comprising at least one PPARδ agonist.” Theterm “or” refers to a single element of stated alternative elements or acombination of two or more elements, unless the context clearlyindicates otherwise. As used herein, “comprises” means “includes.” Thus,“comprising A or B,” means “including A, B, or A and B,” withoutexcluding additional elements. Dates of GenBank® Accession Nos. referredto herein are the sequences available at least as early as Apr. 4, 2014.All references, including patents and patent applications, and GenBank®Accession numbers cited herein, are incorporated by reference.

Unless explained otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood to one of ordinaryskill in the art to which this disclosure belongs. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present disclosure, suitable methods andmaterials are described below. The materials, methods, and examples areillustrative only and not intended to be limiting.

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

All groups stated herein are understood to include both substituted andunsubstituted forms unless specifically stated otherwise, or contextindicates otherwise. “Substituted” means that one or more hydrogen atomsof the specified group or moiety is each, independently of one another,replaced with the same or a different non-hydrogen substituent.

In some embodiments, exemplary substituent groups can include thoselisted below:

Substituents for aliphatic, heteroaliphatic, cycloaliphatic and/orheterocycloaliphatic moieties can be one or more of a variety of groupsselected from, but not limited to, —OR′, oxo, ═NR′, ═N—OR′, —NR′R″,—SR′, halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NRSO₂R′, —CN, and —NO₂ in a number ranging from zero to (2m′+l) or(2m′-1), where m′ is the total number of carbon atoms in such moiety.R′, R″, R′″, and R″″ each independently refer to hydrogen, aliphatic,heteroaliphatic, cycloaliphatic, heterocycloaliphatic, or aryl groups.In some embodiments, R′, R″, R′″, and R″″ can independently refer toaliphatic, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl groups. Whena compound includes more than one R′, R″, R′″, or R″″ group, forexample, each of the R′, R″, R′″, or R″″ groups can be independentlyselected relative to the remaining R′, R″, R′″, and R″″ group(s). Insome embodiments, when R′ and R″ are attached to the same atom, such asa nitrogen atom, they can be combined to form a cyclic structure, suchas a 4-, 5-, 6-, or 7-membered heterocyclic ring.

Substituents for aryl and heteroaryl groups may be selected from, forexample: —OR′, —NR′R″, —SR′, halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NRSO₂R′, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, andfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total number ofopen valences on the aromatic ring system; and where R′, R″, R′″, andR″″ are independently refer to hydrogen, aliphatic, heteroaliphatic,cycloaliphatic, heterocycloaliphatic, or aryl groups. In someembodiments, R′, R″, R′″, and R″″ can independently refer to alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, orheterocycloalkynyl groups. When a compound includes more than one R′,R″, R′″, or R″″ group, for example, each of the R′, R″, R′″, or R″″groups can be independently selected relative to the remaining R′, R″,R′″, and R″″ group(s).

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloaliphatic, or heterocycloaliphatic groups. Suchring-forming substituents are typically, though not necessarily,attached to a cyclic base structure. In some embodiments, thering-forming substituents are attached to adjacent members of the basestructure. For example, two ring-forming substituents can attached toadjacent atoms of a cyclic base structure to create a fused ringstructure. In other embodiments, the ring-forming substituents can beattached to a single atom of the base structure to create a spirocyclicstructure. In yet another embodiment, the ring-forming substituents areattached to non-adjacent atoms of the base structure Unless otherwisestated, structures depicted herein are also meant to include allstereochemical forms of the structure; such as the R and Sconfigurations for each asymmetric center and/or the m and pconfigurations for each biaryl ring system. Therefore, singlestereochemical isomers, as well as enantiomeric, diastereomeric, andatropisomeric mixtures of the present compounds are within the scope ofthe disclosure.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon,are within the scope of this disclosure.

The compounds of the present disclosure may also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as, for example, tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present disclosure, whether radioactive or not, are encompassedwithin the scope of the present disclosure.

The terms “a,” “an,” or “a(n),” when used in reference to a group ofsubstituents herein, mean at least one.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

The term “alkyl,” means, unless otherwise stated, a straight (i.e.,unbranched) or branched chain, or combination thereof, which may befully saturated, mono- or polyunsaturated and can include di- andmultivalent moieties, having the number of carbon atoms designated (forexample, C₁-C₁₀ includes alkyl groups comprising one to ten carbons).Examples of saturated alkyl groups include, but are not limited to,groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl,isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having at least one double bond or atleast one triple bond. Examples of unsaturated alkyl groups include, butare not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl,2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and3-propynyl, 3-butynyl, and the higher homologs and isomers. An “alkoxy”group is an alkyl group attached to the remainder of the molecule via anoxygen linker.

The term “aliphatic” refers to a hydrocarbon-based compound, or a moietythereof, and can include alkanes, alkenes, alkynes, including cyclicversions thereof, (such as cycloalkyl, cycloalkenyl and cycloalkynyl)and further including straight- and/or branched-chain arrangements, andall stereo and positional isomers as well. Unless expressly statedotherwise, an aliphatic group contains at least one carbon atom.

“Alkenyl” refers to straight chain or branched hydrocarbyl groups havingfrom 2 to 10 carbon atoms, and in some embodiments 2 to 8 carbon atoms,and having at least 1 double bond. Such groups are exemplified, forexample, bi-vinyl, allyl, and but-3-en-1-yl. Included within this termare the cis and trans isomers or mixtures of these isomers, unlessotherwise specified. The term “alkenylene” refers to a divalent moietyderived from an alkenyl.

“Alkynyl,” by itself or as part of another substituent, refers tostraight chain or branched hydrocarbyl groups having from 2 to 10 carbonatoms, and in some embodiments 2 to 8 carbon atoms, and having at least1 site of triple bond unsaturation. Such groups are exemplified, forexample, by ethynyl, 1-propynyl and 2-propynyl. The term “alkynylene”refers to a divalent moiety derived from an alkynyl.

The term “heteroaliphatic” refers to an aliphatic compound or grouphaving at least one heteroatom. For example, in some embodiments, one ormore carbon atoms has been replaced with an atom having at least onelone pair of electrons. Heteroaliphatic compounds or groups may bebranched or unbranched, cyclic or acyclic, and can include“heterocycle,” “heterocyclyl,” “heterocycloaliphatic,” or “heterocyclic”groups.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, consisting of at least one carbon atom and atleast one heteroatom selected from the group consisting of O, N, P, Si,and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized, and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N, P, S, and Si may be placed at any interior positionof the heteroalkyl group or at the position at which the alkyl group isattached to the remainder of the molecule. Examples include, but are notlimited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and—CN. Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, at least a divalent moietyderived from heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). As described above, heteroalkyl groups, as used herein,include those groups that are attached to the remainder of the moleculethrough a heteroatom, such as —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′,and/or —SO₂R′. Where “heteroalkyl” is recited, followed by recitationsof specific heteroalkyl groups, such as —NR′R″ or the like, it will beunderstood that the terms heteroalkyl and —NR′R″ are not redundant ormutually exclusive. Rather, the specific heteroalkyl groups are recitedto add clarity. Thus, the term “heteroalkyl” should not be interpretedherein as excluding specific heteroalkyl groups, such as —NR′R″ or thelike.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively.

Additionally, for heterocycloalkyl, a heteroatom can occupy the positionat which the heterocycle is attached to the remainder of the molecule.Examples of cycloalkyl include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl,cycloheptyl, and the like. Examples of heterocycloalkyl include, but arenot limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A“cycloalkylene” and a “heterocycloalkylene,” alone or as part of anothersubstituent, means at least a divalent moiety derived from a cycloalkyland heterocycloalkyl, respectively.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “amino,” refers to a chemical functional group —N(R¹)R¹¹ whereR¹ and R¹¹ are independently hydrogen, aliphatic, alkyl, heteroalkyl,haloalkyl, aliphatic, heteroaliphatic, aryl (such as phenyl or benzyl),heteroaryl, or other functionality. A “primary amino” group is —NH₂. Theterm “aminocarbonyl” refers to a chemical functional group —C(O)-amino,where amino is as defined herein. A primary aminocarbonyl is —CONH₂.

The term “cyano” refers to the chemical functional group —CN.

The term “carboxyl,” “carboxylic acid” or “carboxy” refers to thechemical functional group —CO₂H.

The term “carboxyl ester,” “carboxylic acid ester,” or “carboxy ester”refers to the chemical functional group —CO₂R where R is aliphatic,alkyl, heteroalkyl, haloalkyl, aliphatic, heteroaliphatic, aryl (such asphenyl or benzyl), heteroaryl, or other functionality.

The term “aminosulfonyl” refers to a chemical function group —SO₂-amino,where amino is as defined herein. A primary aminosulfonyl is —SO₂NH₂.

The term “acyl” means, unless otherwise stated, —C(O)R where R is analiphatic, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, orheteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (e.g., from 1 to 5, typically 1 to 3, rings) that arefused together (i.e., a fused ring aryl) or linked covalently. A fusedring aryl refers to multiple rings fused together wherein at least oneof the fused rings is an aryl ring. The term “heteroaryl” refers to arylgroups (or rings) that contain at least one heteroatom, typically N, O,and S. For certain embodiments, heteroatoms, such as the nitrogen andsulfur atoms, are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. Thus, the term “heteroaryl” includes fused ringheteroaryl groups (e.g., multiple rings fused together wherein at leastone of the fused rings is a heteroaromatic ring). A 5,6-fused ringheteroaryl refers to two rings fused together, wherein one ring has 5members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. Likewise, a 6,6-fused ring heteroaryl refers totwo rings fused together, wherein one ring has 6 members and the otherring has 6 members, and wherein at least one ring is a heteroaryl ring.And a 6,5-fused ring heteroaryl refers to two rings fused together,wherein one ring has 6 members and the other ring has 5 members, andwherein at least one ring is a heteroaryl ring. A heteroaryl group canbe attached to the remainder of a molecule through a carbon orheteroatom. Non-limiting examples of aryl and heteroaryl groups includephenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl,2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl,5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,4-benzoxadiazolyle, 5-benzoxodiazole, benzofuran, benzofuranone,benzothiophene, indole, indoline, indolinone 3-quinolyl, and 6-quinolyl.Substituents for each of the above noted aryl and heteroaryl ringsystems are selected from the group of acceptable substituents describedbelow. “Arylene” and a “heteroarylene,” alone or as part of anothersubstituent, mean at least a divalent moiety derived from an aryl andheteroaryl, respectively.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose moieties in which an aryl group is attached to an aliphatic oralkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like)including those aliphitc or alkyl groups in which a carbon atom (e.g., amethylene group) has been replaced by, for example, an oxygen atom(e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, andthe like).

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylsulfonyl,” as used herein, means a moiety having theformula —S(O₂)—R′, where R′ is an aliphatic, alkyl group as definedabove. R′ may have a specified number of carbons (e.g., “C₁-C₄alkylsulfonyl”).

The terms “carboxyl bioisosteric,” or “carboxyl bioisostere” refer to agroup with similar physical or chemical properties to a carboxyl groupthat produce broadly similar biological properties, but which may reducetoxicity or modify the activity of the compound, and may alter themetabolism of the compound. Exemplary carboxyl bioisosteres include, butare not limited to,

where X⁷, Y⁷, and Z⁷ are each independently selected from N, CH₂ or CO;

where X⁸ is selected from O, S or NMe;

where X⁹ is selected from O, N, S, CH or CH₂;

Additional carboxyl bioisosteric groups contemplated by the presentdisclosure include

The term “pharmaceutically acceptable salts” is meant to include saltsof active compounds which are prepared with relatively nontoxic acids orbases, depending on the particular substituents found on the compoundsdescribed herein. When compounds of the present disclosure containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable solvent.Examples of pharmaceutically acceptable base addition salts include, byway of example and without limitation, sodium salts, potassium salts,calcium salts, ammonium salts, organic amino salts, or magnesium salts,or a similar salt. When compounds of the present disclosure containrelatively basic functionalities, acid addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amountof the desired acid, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts includethose derived from inorganic acids like hydrochloric, hydrobromic,nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids, such as arginate and the like, andsalts of organic acids, like glucuronic or galactunoric acids and thelike (see, for example, Berge et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 1977, 66, 1-19). Certain specific compounds ofthe present disclosure contain both basic and acidic functionalitiesthat allow the compounds to be converted into either base or acidaddition salts.

Thus, the compounds provided herein can exist as salts withpharmaceutically acceptable acids. The present disclosure includes suchsalts. Examples of such salts include hydrohalides, such ashydrochlorides and hydrobromides, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates,(−)-tartrates or mixtures thereof including racemic mixtures,succinates, benzoates and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those of ordinary skillin the art.

The neutral forms of the compounds are in some examples regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compound maydiffer from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present disclosure includes compounds ina prodrug form.

Prodrugs of the compounds described herein are those compounds thatreadily undergo chemical changes under physiological conditions toprovide the compounds herein. Additionally, prodrugs can be converted tothe compounds of the present disclosure by chemical or biochemicalmethods in an ex vivo environment. For example, prodrugs can be slowlyconverted to the compounds of the present disclosure when placed in atransdermal patch reservoir with a suitable enzyme or chemical reagent.

Certain compounds provided herein can exist in unsolvated forms as wellas solvated forms, including hydrated forms. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of the present disclosure. Certain compounds provided herein canexist in multiple crystalline or amorphous forms. In general, allphysical forms are equivalent for the uses contemplated by the presentdisclosure and are intended to be within the scope of the presentdisclosure.

The terms “administer,” “administering,” “administration,” and the like,as used herein, refer to methods that may be used to enable delivery ofcompositions to the desired site of biological action. These methodsinclude, but are not limited to, intraarticular (in the joints),intravenous, intramuscular, intratumoral, intradermal, intraperitoneal,subcutaneous, orally, topically, intrathecally, inhalationally,transdermally, rectally, and the like. Administration techniques thatcan be employed with the agents and methods described herein are foundin e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (currentedition), Mack Publishing Co., Easton, Pa.

As used herein, the terms “co-administration,” “administered incombination with,” and their grammatical equivalents, are meant toencompass administration of two or more therapeutic agents to a singlesubject, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different times. In some embodiments the one or morecompounds described herein will be co-administered with other agents.These terms encompass administration of two or more agents to thesubject so that both agents and/or their metabolites are present in thesubject at the same time. They include simultaneous administration inseparate compositions, administration at different times in separatecompositions, and/or administration in a composition in which bothagents are present. Thus, in some embodiments, the compounds describedherein and the other agent(s) are administered in a single composition.In some embodiments, the compounds described herein and the otheragent(s) are admixed in the composition.

The term “effective amount” or “therapeutically effective amount” refersto the amount of an active agent (such as one or more compounds providedherein alone, in combination, or potentially in combination with othertherapeutic agent(s)) sufficient to induce a desired biological result.That result may be amelioration or alleviation of the signs, symptoms,or causes of a disease, or any other desired alteration of a biologicalsystem. The term “therapeutically effective amount” is used herein todenote any amount of a therapeutic that causes an improvement in adisease condition. The amount can vary with the condition being treated,the stage of advancement of the condition, and the type andconcentration of formulation applied. Appropriate amounts in any giveninstance will be readily apparent to those of ordinary skill in the artor capable of determination by routine experimentation.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably. Therapeutic benefit meanseradication or amelioration of the underlying disorder being treated.Also, a therapeutic benefit is achieved with eradication or ameliorationof one or more of the physiological symptoms associated with theunderlying disorder, such that an improvement is observed in thesubject, notwithstanding that the subject may still be afflicted withthe underlying disorder.

The terms “prevent,” “preventing” or “prevention,” and other grammaticalequivalents as used herein, include preventing additional symptoms,preventing the underlying metabolic causes of symptoms, inhibiting thedisease or condition, e.g., arresting the development of the disease orcondition and are intended to include prophylaxis. The terms furtherinclude achieving a prophylactic benefit. For prophylactic benefit, thecompositions are optionally administered to a subject at risk ofdeveloping a particular disease, to a subject reporting one or more ofthe physiological symptoms of a disease, or to a subject at risk ofreoccurrence of the disease. Preventing the disease can result in thedelay or prevention of development of one or more clinical symptoms ofthe disease by administration of a protective composition prior to theinduction of the disease; suppressing the disease, that is, causing theclinical symptoms of the disease not to develop by administration of aprotective composition after the inductive event but prior to theclinical appearance or reappearance of the disease.

“Inhibiting” the disease refers to arresting the development of clinicalsymptoms by administration of a protective composition after theirinitial appearance; preventing re-occurring of the disease and/orrelieving the disease, that is, causing the regression of clinicalsymptoms by administration of a protective composition after theirinitial appearance.

The terms “subject,” “individual,” or “patient,” are usedinterchangeably. These terms refer to a vertebrate, such as a mammal,for example a human. Mammals include, but are not limited to, murines,simians, humans, farm animals, sport animals, and pets. Tissues, cellsand their progeny of a biological entity obtained in vitro or culturedin vitro are also encompassed. In some embodiments, the subjectadministered one or more of the compounds provided herein is a sedentary(such as one with no or irregular physical activity, for example one whosits or remains inactive for most of the day with little or no exercise)or immobilized subject (such as a subject confined to a wheelchair,hospital bed, and the like, or one who has a body part in a cast, suchas a leg or arm). In other embodiments, the subject administered one ormore of the compounds provided herein is an ambulatory or exercisedsubject, such as a subject in rehab potentially after surgery, or agedor obese subjects. In some embodiments, exercise can include low impactexercise, spanning from once or twice per day. Examples of low impactexercise can include swimming and light to moderate resistance training.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the formulation and/oradministration of an active agent to and/or absorption by a subject andcan be included in the compositions of the present disclosure withoutcausing a significant adverse toxicological effect on the subject.Non-limiting examples of pharmaceutically acceptable excipients includewater, NaCl, normal saline solutions, lactated Ringer's, normal sucrose,normal glucose, binders, fillers, disintegrants, lubricants, coatings,sweeteners, flavors, salt solutions (such as Ringer's solution),alcohols, oils, gelatins, carbohydrates such as lactose, amylose orstarch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine,and colors, and the like. Such preparations can be sterilized and, ifdesired, mixed with auxiliary agents such as lubricants, preservatives,stabilizers, wetting agents, emulsifiers, salts for influencing osmoticpressure, buffers, coloring, and/or aromatic substances and the likethat do not deleteriously react with or interfere with the activity ofthe compounds provided herein. One of ordinary skill in the art willrecognize that other pharmaceutical excipients are suitable for use withdisclosed compounds.

The term “preparation” is intended to include formulations of an activecompound with another material, such as an encapsulating material as acarrier to provide a capsule. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges canbe used as solid dosage forms suitable for oral administration.

The term “peroxisome proliferator-activated receptor delta (PPARδ)”refers to the PPARδ protein (or its coding or gene sequence), a memberof a subfamily of nuclear hormone receptors. Ligands of PPARδ canpromote myoblast proliferation after injury, such as injury to skeletalmuscle. PPARδ (OMIM 600409) sequences are publically available, forexample from GenBank® sequence database (e.g., accession numbersNP_(—)001165289.1 (human, protein) NP_(—)035275 (mouse, protein),NM_(—)001171818 (human, nucleic acid) and NM_(—)011145 (mouse, nucleicacid)).

II. Compounds

Disclosed herein are embodiments of a compound having general Formula 1

With reference to Formula 1, ring A is selected from a cycloalkylene,heterocycloalkylene, arylene or heteroarylene. Further with respect toring A, in certain embodiments when ring A is phenyl, the L⁵ group andthe X-L²-Z group typically are positioned ortho or para to each other.In further embodiments wherein ring A is phenyl, the L⁵ group and theX-L²-Z are not positioned meta to each other unless L⁵ forms a fusedring system with ring A. Exemplary ring A embodiments are illustratedbelow:

In an independent embodiment, ring A is selected from

Ring B is selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl,cycloalkylene, heterocycloalkylene, arylene or heteroarylene. Exemplaryring B embodiments are illustrated below:

In an independent embodiment, ring B is selected from

Each R² independently is selected from deuterium, halogen, aryl,heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO₂, OH, amino,amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, SO₃H, oracyl.

In some embodiments R² may be halogen selected from Cl, F, I, Br;heteroaliphatic selected from alkyloxy (e.g., O(CH₂)₀₋₅CH₃),haloalkyloxy (e.g., O(CH₂)₀₋₅CF₃, O(CH₂)₀₋₅CHF₂), cycloalkyloxy (e.g.,O-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl), cyano,haloalkyl (e.g., CF₃), CD₃, OCD₃; aliphatic, selected from alkyl,alkenyl, alkynyl; amino selected from N(R³⁰)₂ wherein each R³⁰ may beselected from hydrogen, aliphatic, aryl, or cycloaliphatic; heterocyclicselected from piperidinyl, piperazinyl, pyrrolidinyl, 4H-pyranyl,4H-furanyl, 4H-thiophene, 4H-thiopyranyl, azetidinyl, oxetanyl,piperidinone, 4H-pyranone, 4H-furanone, 4H-pyrrolidone, 4H-thiopyranone,4H-thiophenone, and any such groups comprising one or more sites ofunsaturation; aryl selected from phenyl, naphthalene, anthracene, orphenanthracene; cycloaliphatic selected from cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, bicyclononane, bicycloheptane,and any such groups comprising one or more sites of unsaturation;heteroaryl selected from pyridinyl, furanyl, thiophene, pyrrole,oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiodiazole,diazole, triazole, or tetrazole. In some embodiments, at least two R²groups are present and adjacent to each other and join together to forma fused ring system with ring B. In such embodiments, each R² can beselected to form a fused heterocylic, cyclicaliphatic, heteroaryl, oraryl ring system. Exemplary R² groups are provided below:

With continued reference to Formula 1:

n is from 0 to 5;

m is from 0 to 4;

each R²² independently is selected from deuterium, halogen, aryl,heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO₂, OH, amino,amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, SO₃H, oracyl. In some embodiments R²² may be halogen selected from Cl, Fl, I,Br; heteroaliphatic selected from alkyloxy (e.g., O(CH₂)₀₋₅CH₃),haloalkyloxy (e.g., O(CH₂)₀₋₅CF₃, O(CH₂)₀₋₅—CHF₂), cycloalkyloxy (e.g.,O-cyclopropyl, O-cyclobutyl, O-cyclopentyl, O-cyclohexyl), cyano,haloalkyl (e.g., CF₃), CD₃, OCD₃; aliphatic, selected from alkyl,alkenyl, alkynyl; amino selected from N(R¹R¹¹)₂ wherein each R³⁰ may beselected from hydrogen, aliphatic, aryl, or cycloaliphatic; heterocyclicselected from piperidinyl, piperazinyl, pyrrolidinyl, 4H-pyranyl,4H-furanyl, 4H-thiophene, 4H-thiopyranyl, azetidinyl, oxetanyl,piperidinone, 4H-pyranone, 4H-furanone, 4H-pyrrolidone, 4H-thiopyranone,4H-thiophenone, and any such groups comprising one or more sites ofunsaturation; aryl selected from phenyl, naphthalene, anthracene, orphenanthracene; cycloaliphatic selected from cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, bicyclononane, bicycloheptane,and any such groups comprising one or more sites of unsaturation;heteroaryl, selected from pyridinyl, furanyl, thiophene, pyrrole,oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiodiazole,diazole, triazole, or tetrazole. Exemplary R²² groups are providedbelow:

X is O, NR³⁰, sulfonyl, or S, where R³⁰ is selected from H or aliphatic,aryl, or cycloaliphatic.

L⁵ is selected from a bond, aliphatic, heteroaliphatic, arylene,heteroarylene, cycloalkylene, or heterocycloalkylene. Exemplary L⁵groups are illustrated below:

In an independent embodiment, L⁵ is selected from

Each L² is selected from a bond, aliphatic, heteroaliphatic, arylene,heteroarylene, cycloalkylene, heterocycloalkylene or —CR²³R²⁴—, whereinR²³ and R²⁴ each independently is selected from H, deuterium, halogen,aliphatic, alkyl, —C(O)OR²⁵ or —C(O)NR²⁵R²⁶, wherein R²⁵ and R²⁶ eachindependently is hydrogen or aliphatic, alkyl. Exemplary L² groups areprovided below. In any of the embodiments disclosed herein for L², theL² group can be halogenated. In some embodiments, the L² group may befluorinated.

Z is selected from R¹L¹C(O)— or a carboxyl bioisostere, wherein L¹ is abond or —NR³⁰—, and R¹ is hydrogen, aliphatic, —OR^(1A), —NR^(1A)R^(1B),—C(O)R^(1A), —S(O)₂R^(1A), —C(O)OR^(1A), —S(O)₂NR^(1A)R^(1B) or—C(O)NR^(1A)R^(1B), wherein R^(1A), R^(1B) each independently ishydrogen or aliphatic, typically aliphatic, alkyl.

In some embodiments, Z is a carboxyl bioisostere, and in certainembodiments, Z is selected from

where X⁷, Y⁷, and Z⁷ each independently is selected from N, CH₂ or CO;X⁸ is selected from O, S or NMe; and X⁹ is selected from O, N, NH, S, CHor CH₂.

In an independent embodiment, Z is selected from

In certain embodiments the compound has a Formula 1, wherein:

if L⁵ is —CH₂N(L⁴R³)C(O)—, L⁴R³ is n-propyl or isopropyl, ring A isphenyl, and n is 1 then R² is not 4-bromo or 4-benzo[d][1,3]dioxole;

if L⁵ is —CH₂CH₂N(L⁴R³)C(O)NH—, X is S, and L⁴R³ is an unbranchedaliphatic or alkyl chain, then L⁴R³ is a C₁-C₆ unbranched aliphatic oralkyl chain;

if L⁵ is —CH₂CH₂N(L⁴R³)C(O)NH—, X is S, and L⁴ is an unbranchedaliphatic or alkyl chain, then R³ is not a cyclohexyl;

if L⁵ is —CH₂N(L⁴R³)C(O)—, L⁴R³ is isopropyl, ring A and ring B are bothphenyl, and n is 1 then the —XL²Z moiety is ortho or para to L⁵, or L⁵forms a fused ring with ring A.

In particular disclosed embodiments, compounds of Formula 1 are not anyof the following compounds:4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}aceticacid (also known as “GW501516,” “GW-501,516,” “GW1516,” “GW” orGSK-516), having a structure:

{4-[({2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-1,3-thiazol-5-Yl}methyl)sulfanyl]-2-methylphenoxy}aceticacid (also known as “GW 0742), having a structure:

2-((4-(2-(3-(2,4-difluorophenyl)-1-heptylureido)ethyl)phenyl)thio)-2-methylpropanoicacid (also known as GW9578), having a structure:

2-((4-(2-(3-cyclohexyl-1-(4-cyclohexylbutyl)ureido)ethyl)phenyl)thio)-2-methylpropanoicacid (also known as GW7647), having a structure:

(S)-2-((2-(methoxycarbonyl)phenyl)amino)-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoicacid (also known as GW7845), having a structure:

2-((4-(2-(1-(4-cyclohexylbutyl)-3-(4-methoxyphenyl)ureido)ethyl)phenyl)thio)-2-methylpropanoicacid, having a structure:

2-((4-(2-(1-(4-cyclohexylbutyl)-3-(3-methoxyphenyl)ureido)ethyl)phenyl)thio)-2-methylpropanoicacid, having a structure:

2-((4-(2-(1-(4-cyclohexylbutyl)-3-(2-methoxyphenyl)ureido)ethyl)phenyl)thio)-2-methylpropanoicacid, having a structure:

ethyl 6-(2-((4-bromo-N-propylbenzamido)methyl)phenoxy)hexanoate, havinga structure

ethyl 6-(4-((4-bromo-N-propylbenzamido)methyl)phenoxy)hexanoate, havinga structure

ethyl6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoate,having a structure

ethyl6-(4-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoate,having a structure

6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoicacid, having a structure

6-(4-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoicacid, having a structure

ethyl6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate,having a structure

ethyl6-(4-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate,having a structure

6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid, having a structure

6-(4-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid, having a structure

In some embodiments, disclosed compounds can have a Formula 2 and/orFormula 3, illustrated below.

With reference to either one of Formula 2 and/or Formula 3, rings A andB, X, L², Z, R², R²², m and n are as recited above; L³ can be selectedfrom a bond, aliphatic, —C(O)—, alkylC(O)—, —C(O)alkyl-, or sulfonyl; L⁴can be selected from a bond, aliphatic, heteroaliphatic, arylene,heteroarylene, cycloalkylene, heterocycloalkylene or —CR²³R²⁴—; R³ canbe selected from —OH, —OR^(3A), —NR^(3A)R^(3B), —C(O)R^(3A),—S(O)₂R^(3A), —C(O)OR^(3A), —S(O)₂NR^(3A)R^(3B), or —C(O)NR^(3A)R^(3B),aliphatic, heteroaliphatic, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, or R³ can be joined with an atom of ring B to form a fusedring system or may be joined with an atom of L³ to form a heterocyclicring system; R^(3A), R^(3B) each independently is hydrogen or aliphatic,typically alkyl. Also with reference to Formulas 2 and/or 3, the-L³N(L⁴R³)L³- group may have any of the following formulas, which may beincorporated in any of the general formulas provided herein.

With reference to these embodiments, each R³¹ and R³² independently maybe selected from hydrogen, aliphatic, heteroaliphatic, or any one of R³¹and R³² may be joined with R³ to form a ring, such as a four-, five-,six-, or seven-membered ring system, which may be saturated orunsaturated, or may be joined with an atom of ring B to form a fusedring system, such as a 5-6 fused ring system, a 6-6 fused ring system,or a 6-5 fused ring system; and each p independently is 0, 1, 2, 3, 4,or 5.

In some embodiments, disclosed compounds may have a Formula 4 or Formula5, illustrated below.

With reference to either one of Formulas 4 or 5, X, L², Z, L³, ring B,ring A, R², R²², m and n are as provided above. X¹ can be selected fromcarbon, nitrogen, or N-oxide.

In some embodiments, disclosed compounds may have a Formula 6 or Formula7, illustrated below.

With reference to either one of Formulas 6 or 7, X, L², Z, L³, ring B,ring A, R², R²², m and n are as provided above; Z¹ may be selected fromcarbon, oxygen, sulfur, or NR³⁰; and each Y independently is carbon ornitrogen.

In some embodiments, disclosed compounds may have a Formula 8,illustrated below.

With reference to Formula 8, X, L², Z, L³, ring B, ring A, R², R²², mand n are as provided above; X² may be a bond, carbon, oxygen, sulfur,or NR³⁰.

In some embodiments, disclosed compounds may have a Formula 9,illustrated below.

With reference to Formula 9, X, L², Z, L³, ring B, ring A, R², R²², mand n are as provided above; each X³ independently may be nitrogen,carbon, NR³⁰, or oxo; each Y independently may be carbon or NR³⁰.

In yet other embodiments, disclosed compounds may have any one ofFormulas 10-18, illustrated below.

In some embodiments, rings A and B are both phenyl, leading to compoundshaving Formula 19:

In certain embodiments, disclosed compounds can have Formula 20,illustrated below.

In certain particular embodiments of the any of the Formulas providedabove, R^(1A) is hydrogen, aliphatic, or alkyl. R² is halogen, R³ isaliphatic, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl. L¹ is a bond or —NR³⁰— and L², L³ and L⁴ are independently abond or alkylene.

In some examples of compounds, rings A and B are six-membered rings, R′is —OR^(1A) and R² is para to the amide, leading to compounds withFormula 21:

With respect to Formula 21, R^(1A) is hydrogen, aliphatic, or alkyl, R²is halogen, aryl or heteroaryl, R³ is aliphatic, alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —OR^(3A),—NR^(3A)R^(3B), —C(O)OR^(3A), —S(O)₂NR^(3A)R^(3B), or—C(O)NR^(3A)R^(3B). R^(3A) and R^(3B) are independently hydrogen,aliphatic or alkyl. L¹ is a bond or —NR³⁰—, and L², L³ and L⁴ areindependently a bond, alkylene, heteroalkylene, cycloalkylene,heterocycloalkylene or —CR⁹R¹⁰—. R⁹ and R¹⁰ are independently hydrogen,D, F, aliphatic, alkyl or —C(O)R⁷, wherein R⁷ may be hydrogen, halogen,═O (oxo), —CF₃, —CN, —CCl₃, —COOH, —CH₂COOH, —CONH₂, —OH, —SH, —SO₂Cl,—SO₃H, —SO₂NH₂, —NO₂, —NH₂, —NHNH₂, —NHC(O)NHNH₂, —OR^(7A). Q, W, Y, andZ are bonded by a single or double bond such that the resulting ring isaromatic. Q, W, Y, and Z are independently selected from CH, —CR²² or N.R²² is selected from D, F, Cl, aliphatic or alkyl, —CD₃, —CF₃, —OH,—OCH₃, —OCD₃ or —OCF₃. A₁, A₂, A₃, and A₄ are bonded by a single ordouble bond such that the resulting ring is aromatic. A₁, A₂, A₃, and A₄are independently selected from —CR²⁷ or N. R²⁷ is selected from H, D,F, Cl, aliphatic or alkyl, —CD₃, —CF₃, —OH, —OCH₃, —OCD₃ or —OCF₃.

R^(1A) may be hydrogen or aliphatic, typically alkyl. In someembodiments, R^(1A) is C₁-C₂₀ (e.g., C₁-C₆) aliphatic or alkyl. In someembodiments, R^(1A) is C₁-C₁₀ aliphatic or alkyl. In some embodiments,R^(1A) is C₂ aliphatic or alkyl.

R³ may be aliphatic, alkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl. R³ may be C₁-C₂₀ (e.g., C₁-C₆) aliphatic or alkyl, C₃-C₈(e.g., C₅-C₇) cykloalkyl, 3 to 8-membered (e.g., 3 to 6-membered)heterocycloalkyl, C₅-C₁₀ (e.g., C₅-C₆) aryl, or 5 to 10-membered (e.g.,5 to 6-membered) heteroaryl. In some embodiments, R³ is linear orbranched C₁-C₂₀ (e.g., C₁-C₆) aliphatic or alkyl. In some embodiments,R³ is linear aliphatic or alkyl. In other embodiments, R³ is branchedaliphatic or alkyl. In some embodiments, R³ is C₁-C₅ aliphatic or alkyl.In other embodiments, R³ is C₄ aliphatic or alkyl. In other embodiments,R³ is C₃ aliphatic or alkyl. In some embodiments, R³ is branched C₁-C₅aliphatic or alkyl. In other embodiments, R³ is branched C₄ aliphatic oralkyl. In other embodiments, R³ is branched C₃ aliphatic or alkyl.

R³ may be C₃-C₈ (e.g., C₅-C₇) cycloalkyl. In some embodiments, R³ is 3-to 5-membered (i.e. C₃-C₅) cycloalkyl. In some embodiments, R³ is3-membered (i.e. C₃) cycloalkyl. In some embodiments, R³ is 5-membered(i.e. C₅) cycloalkyl.

In other embodiments, R³ is 3- to 8-membered (e.g., 3- to 6-membered)heterocycloalkyl. In some embodiments, R³ is 5- to 6-memberedheterocycloalkyl. In some embodiments, R³ is 5-memberedheterocycloalkyl. In other embodiments, R³ is 6-memberedheterocycloalkyl.

R³ may be C₅-C₁₀ (e.g., C₅-C₆) aryl or 5- to 10-membered (e.g., 5- to6-membered) heteroaryl. In some embodiments, R³ is 5- to 6-memberedaryl. In some embodiments, R³ is 5-membered aryl. In other embodiments,R³ is 6-membered aryl. Thus, in some embodiments, R³ is phenyl. In someembodiments, R³ is 5- to 6-membered heteroaryl. In some embodiments, R³is 5-membered heteroaryl. In other embodiments, R³ is 6-memberedheteroaryl.

L¹, L², L³ and L⁴ may be the same or different and may eachindependently be a bond, —NR³⁰—, —S(O)—, —S(O)₂NH—, —NHS(O)₂—, —C(O)O—,—OC(O)—, —C(O)—, —C(O)NH—, —NH—, —NHC(O)—, —O—, —S—, alkylene,heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, orheteroarylene. In some embodiments, L¹, L², L³ and L⁴ are independentlya bond, —C(O)O—, —OC(O)—, —C(O)—, —C(O)NH—, —NH—,—NHC(O)—, —O—, —S—,alkylene, heteroalkylene, cycloalkylene, heterocykloalkylene, arylene,or heteroarylene.

As described above, L², L³ and L⁴ may be independently a bond or C₁-C₂₀(e.g., C₁-C₆)alkylene. In some embodiments, L² is C₁-C₅ alkylene. Inother embodiments, L² is C₅ alkylene. In some embodiments, L² is linearC₅ alkylene. In other embodiments, L² is branched C₅ alkylene.

As described above, L³ and L⁴ may be independently a bond or C₁-C₂₀(e.g., C₁-C₆)alkylene. Thus, in some embodiments, L³ and L⁴ areindependently a bond or C₁-C₅ alkylene. In some embodiments, L³ is abond or C₁-C₅ alkylene. In some embodiments, L³ is methylene. In otherembodiments, L⁴ is a bond or C₁-C₅ alkylene. In some embodiments, L⁴ ismethylene, ethylene or propylene. In some embodiments, L⁴ is methylene.In other embodiments, L⁴ is ethylene. In other embodiments, L⁴ ispropylene.

In some embodiments, the compound has the structure:

In some embodiments, the compound is selected from:

-   6-(2-((N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   ethyl    6-(2-(1-(4-bromo-N-cyclopropylbenzamido)-2-(tert-butylamino)-2-oxoethyl)phenoxy)hexanoate;-   ethyl    6-(2-(2-(tert-butylamino)-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoate;-   ethyl    6-(2-(2-amino-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoate;-   6-(2-(2-amino-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoic    acid;-   6-(2-(2-(tert-butylamino)-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   N-(2-amino-1-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)-2-oxoethyl)-N-cyclopropyl-[1,1′-biphenyl]-4-carboxamide;-   6-(2-((N-cyclopropyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(pyridin-4-yl)benzamide;-   N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-[1,1′-biphenyl]-4-carboxamide;-   N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(pyridin-3-yl)benzamide;-   N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(1H-pyrazol-4-yl)benzamide;-   N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(thiophen-2-yl)benzamide;-   N-benzyl-4-(furan-2-yl)-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)benzamide;-   N-benzyl-4-(furan-3-yl)-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)benzamide;    6-(2-((N-(sec-butyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(thiophen-3-yl)benzamide;-   6-(2-((N-(sec-butyl)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(sec-butyl)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(sec-butyl)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(sec-butyl)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(sec-butyl)-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(sec-butyl)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(sec-butyl)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-bromo-N-(sec-butyl)benzamido)methyl)phenoxy)hexanoic acid;-   6-(2-((N-(3-morpholinopropyl)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(3-morpholinopropyl)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(3-morpholinopropyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(3-morpholinopropyl)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-3-yl)-N-(3-morpholinopropyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(3-morpholinopropyl)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-(3-morpholinopropyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(3-morpholinopropyl)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(3-morpholinopropyl)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(1H-pyrazol-4-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-3-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-3-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopentyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopentyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopentyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopentyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopentyl-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopentyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopentyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4-(naphthalen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(naphthalen-1-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-3′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-3′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-3′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4′-ethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2′,3′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2′-ethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2′,5′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2′,6′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-3′,5′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-[1,1′:2′,1″-terphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4′-propyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4′-butyl-N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-sec-butyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropylbiphenyl-4-ylcarboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-(2-(4-(furan-2-yl)phenyl)thiazol-5-yl)phenoxy)hexanoic acid;-   6-(2-(cyclopropyl(4-(furan-2-yl)benzyl)carbamoyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2-oxoindoline-5-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2-oxo-2,3-dihydrobenzofuran-5-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropylbenzo[c][1,2,5]oxadiazole-5-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-5-(furan-2-yl)thiazole-2-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-[2,3′-bifuran]-5′-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-((4-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)thiophen-3-yl)oxy)hexanoic    acid;-   N-(2-((5-(1H-tetrazol-5-yl)pentyl)oxy)benzyl)-N-cyclopropyl-4-(furan-2-yl)benzamide;-   6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-3-ynoic    acid;-   6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-4-ynoic    acid;-   (Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-3-enoic    acid;-   (E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-4-enoic    acid;-   (E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-2-enoic    acid;-   (Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-4-enoic    acid;-   (Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-2-enoic    acid;-   (E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-3-enoic    acid;-   6-(2-((N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   ethyl    6-(2-(1-(4-bromo-N-cyclopropylbenzamido)-2-(tert-butylamino)-2-oxoethyl)phenoxy)hexanoate;-   ethyl    6-(2-(2-(tert-butylamino)-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoate;-   ethyl    6-(2-(2-amino-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoate;-   6-(2-(2-amino-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoic    acid;-   6-(2-(2-(tert-butylamino)-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   N-(2-amino-1-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)-2-oxoethyl)-N-cyclopropyl-[1,1′-biphenyl]-4-carboxamide;-   6-(2-((N-cyclopropyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(pyridin-4-yl)benzamide;-   N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-[1,1′-biphenyl]-4-carboxamide;-   N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(pyridin-3-yl)benzamide;-   N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(1H-pyrazol-4-yl)benzamide;-   N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(thiophen-2-yl)benzamide;-   N-benzyl-4-(furan-2-yl)-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)benzamide;-   N-benzyl-4-(furan-3-yl)-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)benzamide;-   6-(2-((N-(sec-butyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(thiophen-3-yl)benzamide;-   6-(2-((N-(sec-butyl)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(sec-butyl)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(sec-butyl)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(sec-butyl)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(sec-butyl)-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(sec-butyl)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(sec-butyl)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-bromo-N-(sec-butyl)benzamido)methyl)phenoxy)hexanoic acid;-   6-(2-((N-(3-morpholinopropyl)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(3-morpholinopropyl)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(3-morpholinopropyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(3-morpholinopropyl)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-3-yl)-N-(3-morpholinopropyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(3-morpholinopropyl)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-(3-morpholinopropyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(3-morpholinopropyl)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(3-morpholinopropyl)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(1H-pyrazol-4-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-3-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-3-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopentyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopentyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopentyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopentyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopentyl-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopentyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopentyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4-(naphthalen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-4-(naphthalen-1-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((N-cyclopropyl-2′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-3′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-3′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-3′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4′-ethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2′,3′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2′-ethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2′,5′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2′,6′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-3′,5′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-[1,1′:2′,1″-terphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-4′-propyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4′-butyl-N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-sec-butyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropylbiphenyl-4-ylcarboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-(2-(4-(furan-2-yl)phenyl)thiazol-5-yl)phenoxy)hexanoic acid;-   6-(2-(cyclopropyl(4-(furan-2-yl)benzyl)carbamoyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropyl-2-oxoindoline-5-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-cyclopropylbenzo[c][1,2,5]oxadiazole-5-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-((4-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)thiophen-3-yl)oxy)hexanoic    acid;-   N-(2-((5-(1H-tetrazol-5-yl)pentyl)oxy)benzyl)-N-cyclopropyl-4-(furan-2-yl)benzamide;-   6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-3-ynoic    acid;-   6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-4-ynoic    acid;-   (Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-3-enoic    acid;-   (E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-4-enoic    acid;-   (E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-2-enoic    acid;-   (Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-4-enoic    acid;-   (Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-2-enoic    acid;-   (E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-3-enoic    acid;-   N-cyclopropyl-N-(2-((5-(2,4-dioxothiazolidin-5-yl)pentyl)oxy)benzyl)-4-(furan-2-yl)benzamide;-   N-cyclopropyl-N-(2-((5-(2,4-dioxooxazolidin-5-yl)pentyl)oxy)benzyl)-4-(furan-2-yl)benzamide;-   N-cyclopropyl-4-(furan-2-yl)-N-(2-((5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)pentyl)oxy)benzyl)benzamide;-   N-cyclopropyl-4-(furan-2-yl)-N-(2-((5-(3-hydroxyisothiazol-5-yl)pentyl)oxy)benzyl)benzamide;-   N-cyclopropyl-4-(furan-2-yl)-N-(2-((5-(3-hydroxyisoxazol-5-yl)pentyl)oxy)benzyl)benzamide;-   N-cyclopropyl-N-(2-((5-(2,5-dioxo-2,5-dihydro-1H-imidazol-4-yl)pentyl)oxy)benzyl)-4-(furan-2-yl)benzamide;-   N-cyclopropyl-N-(2-((5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)pentyl)oxy)benzyl)-4-(furan-2-yl)benzamide;-   N-cyclopropyl-4-(furan-2-yl)-N-(2-((5-(6-hydroxy-4-oxo-4H-1,3-dioxin-2-yl)pentyl)oxy)benzyl)benzamide;-   6-(2-((4-cyclopropoxy-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-methylbenzamido)methyl)phenoxy)hexanoic acid;-   6-(2-((4-(cyclopentylethynyl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-((1-methylazetidin-3-yl)ethynyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-chloro-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid;-   6-(2-((N-isopropyl-4-methoxybenzamido)methyl)phenoxy)hexanoic acid;-   6-(2-((4-(dimethylamino)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(trifluoromethoxy)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-acetyl-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid;-   6-(2-((N-isopropyl-4-(methylsulfonyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((3′-(furan-3-yl)-N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-fluoro-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid;-   6-(2-((N-isopropyl-4-(4-methoxytetrahydro-2H-pyran-4-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(3,3,3-trifluoroprop-1-yn-1-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(oxetan-3-ylethynyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(cyclobutylethynyl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(1-(trifluoromethyl)cyclopropyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(1-methoxycyclopropyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(tetrahydro-2H-pyran-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(4-methylbicyclo[2.2.2]octan-1-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(6-oxo-1,6-dihydropyridin-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(oxetan-2-ylethynyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(4-(trifluoromethyl)bicyclo[2.2.2]octan-1-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(4-phenylbicyclo[2.2.2]octan-1-yl)benzamido)methyl)phenoxy)hexanoic    acid-   6-(2-((4-cyano-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid;-   6-(2-((N-isopropyl-4-(oxetan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(pyrrolidin-1-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((5-(furan-2-yl)-N-isopropylpicolinamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((2-(furan-2-yl)-N-isopropylthiazole-5-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-isopropyl-2,5-dioxopiperazine-1-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-(((4-(furan-2-yl)-N-isopropylphenyl)sulfonamido)methyl)phenoxy)hexanoic    acid;-   6-(2-(2-((4-(furan-2-yl)phenyl)(isopropyl)amino)-2-oxoethyl)phenoxy)hexanoic    acid;-   6-(2-((6-(furan-2-yl)-N-isopropylnicotinamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)benzyl)(isopropyl)carbamoyl)phenoxy)hexanoic    acid;-   6-(2-((2-(furan-2-yl)-N-isopropyloxazole-5-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-(3-((4-(furan-2-yl)phenyl)(isopropyl)amino)-3-oxopropyl)phenoxy)hexanoic    acid;-   6-(2-((2-fluoro-4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((3-fluoro-4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((1-(furan-2-yl)-N-isopropylpiperidine-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((5-(furan-2-yl)-N-isopropylisoxazole-3-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-isopropylcyclohexane-1-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-(((6-(furan-2-yl)-1H-indazol-3-yl)(isopropyl)amino)methyl)phenoxy)hexanoic    acid;-   6-(2-((5-(furan-2-yl)-N-isopropylthiazole-2-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-2-methylbenzofuran-6-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-2-methylbenzofuran-5-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((7-(furan-2-yl)-4-oxoquinazolin-3(4H)-yl)methyl)phenoxy)hexanoic    acid;-   6-(2-((1-(furan-2-yl)-N-isopropyl-2-oxopiperidine-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((5-(furan-2-yl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((5-(furan-2-yl)-N-isopropyl-1-methyl-1H-pyrazole-3-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((5-(furan-2-yl)-N-isopropyl-3,6-dioxopiperazine-2-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-isopropylpiperidine-1-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-(2,2,2-trifluoroethyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-(2-methoxyethyl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic acid;-   6-(2-((4-(furan-2-yl)-N-(oxetan-3-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((2-(4-(furan-2-yl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(2-cyanopropan-2-yl)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((2-(4-(furan-2-yl)phenyl)-4-methyl-1H-imidazol-1-yl)methyl)phenoxy)hexanoic    acid;-   6-(2-(2-(4-(furan-2-yl)phenyl)-1-methyl-1H-imidazol-5-yl)phenoxy)hexanoic    acid;-   6-(2-((6-(furan-2-yl)-3-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-hydroxybenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((3-(4-(furan-2-yl)phenyl)-5-methylisoxazol-4-yl)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-methoxybenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(cyclopropylmethyl)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(1-cyclopropylethyl)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-(1-(4-(furan-2-yl)benzoyl)pyrrolidin-2-yl)phenoxy)hexanoic    acid;-   6-(2-(1-(4-(furan-2-yl)benzoyl)azetidin-2-yl)phenoxy)hexanoic acid;-   6-(2-(1-(4-(furan-2-yl)benzoyl)piperidin-2-yl)phenoxy)hexanoic acid;-   6-(4-bromo-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)-4-methylphenoxy)hexanoic    acid;-   6-(4-fluoro-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(4-cyano-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)-4-methoxyphenoxy)hexanoic    acid;-   6-((3-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-2-yl)oxy)hexanoic    acid;-   6-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-3-yl)oxy)hexanoic    acid;-   6-((3-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-4-yl)oxy)hexanoic    acid;-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)-1-methyl-1H-pyrazol-3-yl)oxy)hexanoic    acid;-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-3-yl)oxy)hexanoic    acid;-   6-((2-(4-(furan-2-yl)benzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)hexanoic    acid;-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)isothiazol-3-yl)oxy)hexanoic    acid;-   6-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)cyclopentyl)oxy)hexanoic    acid;-   6-(4-cyclopropyl-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)cyclohexyl)oxy)hexanoic    acid;-   6-(4-(azetidin-1-yl)-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)-4-(trifluoromethyl)phenoxy)hexanoic    acid;-   N-(2-(4-(2H-tetrazol-5-yl)butoxy)benzyl)-4-(furan-2-yl)-N-isopropylbenzamide;-   7-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)heptanoic    acid;-   2-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)propoxy)acetic    acid;-   5-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethyl)isoxazole-3-carboxylic    acid;-   2-(5-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)methyl)isoxazol-3-yl)acetic    acid;-   2-(4-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)cyclohexyl)acetic    acid;-   5-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)pentanoic    acid;-   3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethoxy)propanoic    acid;-   3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)acetamido)propanoic    acid;-   3-(4-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)methyl)thiazol-2-yl)propanoic    acid;-   3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethyl)cyclobutane-1-carboxylic    acid;-   3-((2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethyl)amino)-3-oxopropanoic    acid;-   3-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)azetidin-1-yl)propanoic    acid;-   6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)heptanoic    acid;-   2-(3-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)methyl)azetidin-1-yl)acetic    acid;-   2-(4-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)methyl)thiazol-2-yl)acetic    acid;-   2-((3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)propyl)thio)acetic    acid;-   2-((3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)cyclopentyl)oxy)acetic    acid;-   1-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)acetyl)pyrrolidine-3-carboxylic    acid;-   1-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethyl)pyrrolidine-3-carboxylic    acid;-   (E)-6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)-4-methylhex-4-enoic    acid;-   (S)-4-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenyl)sulfonyl)-2,3-dihydro-1H-indene-2-carboxylic    acid;-   4-(furan-2-yl)-N-(2-(4-(5-hydroxy-1,3,4-oxadiazol-2-yl)butoxy)benzyl)-N-isopropylbenzamide;-   1-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethyl)azetidine-3-carboxylic    acid;-   2-(4-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)acetic    acid;-   3-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)piperidin-1-yl)propanoic    acid;-   6-(2-((4-(cyclopropylethynyl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-(1-(4-(furan-2-yl)benzyl)-5-methyl-1H-imidazol-2-yl)phenoxy)hexanoic    acid-   6-(2-((4-(4-(furan-2-yl)phenyl)-5-methylisoxazol-3-yl)methyl)phenoxy)hexanoic    acid-   6-(2-((N-benzyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(cyclopropylethynyl)-N-methylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-methyl-4-(3,3,3-trifluoroprop-1-yn-1-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-cyclopropoxy-N-methylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((5-(furan-2-yl)-N-methylpicolinamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((5-(furan-2-yl)-N-methylthiazole-2-carboxamido)methyl)phenoxy)hexanoic    acid;-   3-(2-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)ethoxy)propanoic    acid;-   N-(2-(4-(2H-tetrazol-5-yl)butoxy)benzyl)-4-(furan-2-yl)-N-methylbenzamide;-   6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)heptanoic    acid;-   6-((3-((4-(furan-2-yl)-N-methylbenzamido)methyl)pyridin-2-yl)oxy)hexanoic    acid;-   6-((3-((6-(furan-2-yl)-N-methylnicotinamido)methyl)pyridin-2-yl)oxy)hexanoic    acid;-   6-(4-fluoro-2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)-4-methoxyphenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)-4-methylphenoxy)hexanoic    acid;-   6-(2-((6-(cyclopropylethynyl)-N-isopropylnicotinamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((6-(cyclopropylethynyl)-N-methylnicotinamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(but-2-yn-1-yl)-6-(furan-2-yl)nicotinamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((6-fluoro-N-isopropylnicotinamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((6-fluoro-N-(furan-2-ylmethyl)nicotinamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-benzyl-6-fluoronicotinamido)methyl)phenoxy)hexanoic acid;-   6-(2-(2-(4-(furan-2-yl)phenyl)pyrrolidine-1-carbonyl)phenoxy)hexanoic    acid-   6-(2-((N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-(sec-butyl)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((N-isopropyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic    acid;-   sodium    6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoate;-   2-(2-methyl-4-(((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methyl)thio)phenoxy)acetic    acid;-   (E)-6-(2-((4-(furan-2-yl)-N′-hydroxy-N-isopropylbenzimidamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-((fluoromethyl)thio)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-((difluoromethyl)thio)-N-isopropylbenzamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((4-fluoro-5-(furan-2-yl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl)phenoxy)hexanoic    acid;-   6-(2-((5-(cyclopropylethynyl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl)phenoxy)hexanoic    acid;-   (R)-6-(2-((5-(furan-2-yl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl)phenoxy)heptanoic    acid;-   6-(2-((3-(4-(furan-2-yl)phenyl)-5-methyl-4H-1,2,4-triazol-4-yl)methyl)phenoxy)hexanoic    acid;-   6-(2-((5-(4-(furan-2-yl)phenyl)-3-methyl-1H-1,2,4-triazol-1-yl)methyl)phenoxy)hexanoic    acid;-   6-(2-((2-(5-(furan-2-yl)pyridin-2-yl)-4-methyl-1H-imidazol-1-yl)methyl)phenoxy)hexanoic    acid;-   6-(2-((2-(5-(furan-2-yl)pyridin-2-yl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)hexanoic    acid;-   6-(2-((2-(4-(furan-2-yl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)hexanoic    acid;-   6-(2-((2-(4-(furan-2-yl)phenyl)-4-methyl-1H-imidazol-1-yl)methyl)phenoxy)hexanoic    acid;-   6-(2-(5-(4-(furan-2-yl)phenyl)-1-methyl-1H-imidazol-2-yl)phenoxy)hexanoic    acid;-   6-(2-((4-(furan-2-yl)benzyl)(isopropyl)carbamoyl)phenoxy)hexanoic    acid;-   6-(2-(2-((4-(furan-2-yl)phenyl)(isopropyl)amino)-2-oxoethyl)phenoxy)hexanoic    acid;-   6-(2-(2-(4-(furan-2-yl)phenyl)piperidine-1-carbonyl)phenoxy)hexanoic    acid-   6-(2-(2-(4-(furan-2-yl)phenyl)azetidine-1-carbonyl)phenoxy)hexanoic    acid-   6-(2-((3-(4-(furan-2-yl)benzoyl)isoxazol-4-yl)methyl)phenoxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyrrolidin-3-yl)oxy)hexanoic    acid-   6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)morpholin-3-yl)oxy)hexanoic    acid-   6-(2-(1-(4-(furan-2-yl)benzyl)-4-methyl-1H-imidazol-2-yl)phenoxy)hexanoic    acid

III. Method of Making the Compounds

Disclosed compounds can be prepared to the carboxylic acid or hydroxamicacid at L¹ respectively, as exemplified below and as will be understoodby a person of ordinary skill in the art of organic synthesis. For thepreparation of the corresponding salts, an additional step would beperformed. An exemplary synthesis may include the following 1^(st)reaction step:

An alkylation reaction, specifically an etherification reaction, isperformed where a hydroxyaryl or hydroxyheteroaryl moiety is reactedwith an alkylating agent. For the hydroxyaryl or hydroxyheteroarylmoiety, the ring atoms are CR^(A) or N; and R^(A) is selected from H, D,F, Cl, lower aliphatic or alkyl, —CD₃, —CF₃, —OH, —OCH₃, —OCD₃ or —OCF₃.A suitable exemplary alkylating agent is an alkyl bromideR₁—O-L¹(CO)L²-Br. The reactants are combined in the presence of a molarexcess of a carbonate base (e.g. M=Na, K or Cs). The reaction is carriedout in a polar aprotic solvent with a boiling point >100° C. such asDMF, DMA or DME. Typical reaction concentrations are 0.1 to 1.0M.Reactants are heated to >100 OC, under ambient or elevated pressure,such as with microwave assisted organic synthesis (MAOS), for a periodof time ranging from minutes to hours until both reactants are consumed.Exemplary aldehydes include:

Exemplary linkers include:

where m and n independently are selected from a range of 1-6 and R¹(referred to herein as R^(1A)) is aliphatic, typically alkyl. Generallythe distance between the bromide and the carbonyl carbon is 4-8carbon-carbon bond lengths. Isolation, purification and characterizationof the product aldehyde would be consistent with that typicallypracticed by one of ordinary skill in the art.

An exemplary 2^(nd) step of the reaction process is provided below:

The 2^(nd) reaction step is generally characterized as a reductiveamination reaction of an aldehyde and primary amine, such as R³-L⁴-NH₂,where the reducing nucleophile is L³. L³ can be —H, -D, —CH₃, aliphatic,typically alkyl, and more typically lower alkyl. The reaction conditionsare performed so that monoalkylation is the major product and overalkylation to the tertiary amine is suppressed. Reducing agents andco-solvent reaction additives are numerous, but readily known to thoseof ordinary skill in the art. Some exemplary primary amines comprisingR³ and L⁴ functionalities include:

Solvents typically are chlorinated hydrocarbons, such as CH₂Cl₂, CHCl₃,or 1,2-dichloroethane. Reaction temperature and reaction time varydepending on the reaction temperature selected. As described above, MAOSversions of reductive amination exist.

The 3^(rd) reaction step is generally characterized as a secondary amineacylation reaction. Exemplary acylating reagents include 4-bromobenzoylor 4-bromoheteroaryoyl compounds. X typically is a leaving group, suchas F, Cl, OTf, or similar favorable leaving group.

A₁, A₂, A₃, and A₄ are bonded by a single or double bond such that theresulting ring is aromatic; A₁, A₂, A₃, and A₄ are independentlyselected from —CR¹² or N; R¹² is selected from H, D, F, Cl, lower alkyl,—CD₃, —CF₃, —OH, —OCH₃, —OCD₃ or —OCF₃. Representative examples include:

Typical reagent conditions include using a base, typically anon-nucleophillic base, or a hindered base having attenuatednucleophilicity, in excess molar amounts. Hindered amine bases, such asHunig's base (N,N-diisopropylethylamine), would be a suitable choice, aswill be recognized by a person of ordinary skill in the art. Solventstypically are chlorinated hydrocarbons, such as CH₂Cl₂, CHCl₃, or1,2-dichloroethane. Reaction temperature and reaction time varydepending on the reaction temperature selected. As described above, MAOSversions of secondary amine acylation exist.

The 4^(th) reaction step is generally characterized as a biaryl,aryl-heteroaryl or heteroaryl-heteroaryl coupling reaction mediatedcatalytically by a transition metal or transition metal complex.

Numerous coupling reactions are known to those of ordinary skill in theart. In this embodiment, the coupling reaction could be theSuzuki-Miyaura cross-coupling where X is boronate —B(OH)₂, M ispalladium, L is triphenylphosphine (PPh₃), and n is 4. With Pd(PPh₃)₄ asthe catalyst, the cross-coupling reaction would be carried out in thepresence of a base, such as a Na, K or Cs carbonate, in a ternarysolvent system of DME, EtOH and Water. R² may be any aryl, aryl,heteroaryl, heteroaryl boronic acid, boronate ester or potassiumtrifluroboronate salt in this cross-coupling example. Exemplary R²moieties include:

Reaction temperature and reaction time vary depending on the reactiontemperature selected. As described above, MAOS versions ofcross-coupling reactions exist.

The final step of this exemplary reaction sequence is saponification ofR¹ where L¹ is a bond, thereby converting the carboxylic ester to thecarboxylic acid. Where L¹ is nitrogen, R¹ is deprotected to thehydroxamic acid according to methods known to those of ordinary in theart. This reaction step is as follows:

Typically the base is a hydroxide salt, such as Li, Na, K or Cshydroxide. Suitable solvents include, but are not limited to, water,THF, alcohols, such as methanol, ethanol, propanol or isopropanol, DMF,DMSO, or any combination thereof. Reaction temperature and reaction timevary depending on the reaction temperature selected. As described above,MAOS versions of saponification reactions exist.

Additional formulation of these compounds include converting thecarboxylic acid or hydroxamic acid versions to their complimentarypharmaceutically relevant salts. The various methods for salt formationare known to a person of ordinary skill in the art. An exemplary schemeis provided below.

IV. Pharmaceutical Compositions and Administration

A. Additional Therapeutic Agents

Pharmaceutical compositions are disclosed that include one or morecompounds provided herein (such as 1, 2, 3, 4 or 5 of such compounds),and typically at least one additional substance, such as an excipient, aknown therapeutic other than those of the present disclosure, andcombinations thereof. In some embodiments, the disclosed PPAR agonistscan be used in combination with other agents known to have beneficial,additive or synergistic activity with the disclosed PPAR agonists. Forexample, disclosed compounds can be administered alone or in combinationwith: one or more other PPAR agonists, such as a thiazolidinedione,including rosiglitazone, pioglitazone, troglitazone, and combinationsthereof, or a sulfonylurea agent or a pharmaceutically acceptable saltthereof, such as tolbutamide, tolazamide, glipizide, carbutamide,glisoxepide, glisentide, glibornuride, glibenclamide, gliquidoneglimepiride, gliclazide and the pharmaceutically acceptable salts ofthese compounds, or muraglitazar, farglitazar, naveglitazar,netoglitazone, rivoglitazone, K-111, GW-677954, (−)-Halofenate, acid,arachidonic acid, clofbrate, gemfibrozil, fenofibrate, ciprofibrate,bezafibrate, lovastatin, pravastatin, simvastatin, mevastatin,fluvastatin, indomethacin, fenoprofen, ibuprofen, and thepharmaceutically acceptable salts of these compounds; furtherpharmacologically active substances which having favorable effects onmetabolic disturbances or disorders frequently associated therewith,such as RXR agonists for treating metabolic and cardiovascular diseasesmedicaments, which lower blood glucose; antidiabetics, such as insulinsand insulin derivatives, including Lantus, Apidra, and other fast-actinginsulins, and GLP-1 receptor modulators; active ingredients for treatingdyslipidemias; anti-atherosclerotic medicaments; anti-obesity agents;anti-inflammatory active ingredients; active ingredients for treatingmalignant tumors; anti-thrombotic active ingredients; active ingredientsfor treating high blood pressure; active ingredients for treating heartfailure, and combinations thereof.

Where cancer is being treated, one or more disclosed PPAR agonists canbe used in combination with other agents for treating liquid, solidand/or metastatic tumors. Exemplary chemotherapeutic agents includeagents that interfere with DNA replication, mitosis and chromosomalsegregation, agents that disrupt the synthesis and fidelity ofpolynucleotide precursors, alkylating agents, antimetabolites, cytotoxicantibiotics, vinca alkaloids, tyrosine kinase inhibitors,metalloproteinase and COX-2 inhibitors, cyclophosphamide, cisplatin,docetaxel, paclitaxel, erlotinib, irinotecan, gemcitabine and cisplatin.Other particular examples of chemotherapeutic agents that can be used incombination with the disclosed compounds include alkylating agents, suchas nitrogen mustards (for example, chlorambucil, chlormethine,cyclophosphamide, ifosfamide, and melphalan), nitrosoureas (for example,carmustine, fotemustine, lomustine, and streptozocin), platinumcompounds (for example, carboplatin, cisplatin, oxaliplatin, andBBR3464), busulfan, dacarbazine, mechlorethamine, procarbazine,temozolomide, thiotepa, and uramustine; folic acid (for example,methotrexate, pemetrexed, and raltitrexed), purine (for example,cladribine, clofarabine, fludarabine, mercaptopurine, and tioguanine),pyrimidine (for example, capecitabine), cytarabine, fluorouracil, andgemcitabine; plant alkaloids, such as podophyllum (for example,etoposide, and teniposide); microtubule binding agents (such aspaclitaxel, docetaxel, vinblastine, vindesine, vinorelbine (navelbine)vincristine, the epothilones, colchicine, dolastatin 15, nocodazole,podophyllotoxin, rhizoxin, and derivatives and analogs thereof), DNAintercalators or cross-linkers (such as cisplatin, carboplatin,oxaliplatin, mitomycins, such as mitomycin C, bleomycin, chlorambucil,cyclophosphamide, and derivatives and analogs thereof), DNA synthesisinhibitors (such as methotrexate, 5-fluoro-5′-deoxyuridine,5-fluorouracil and analogs thereof); anthracycline family members (forexample, daunorubicin, doxorubicin, epirubicin, idarubicin,mitoxantrone, and valrubicin); antimetabolites, such ascytotoxic/antitumor antibiotics, bleomycin, rifampicin, hydroxyurea, andmitomycin; topoisomerase inhibitors, such as topotecan and irinotecan;photosensitizers, such as aminolevulinic acid, methyl aminolevulinate,porfimer sodium, and verteporfin, enzymes, enzyme inhibitors (such ascamptothecin, etoposide, formestane, trichostatin and derivatives andanalogs thereof), kinase inhibitors (such as imatinib, gefitinib, anderolitinib), gene regulators (such as raloxifene, 5-azacytidine,5-aza-2′-deoxycytidine, tamoxifen, 4-hydroxytamoxifen, mifepristone andderivatives and analogs thereof); and other agents, such asalitretinoin, altretamine, amsacrine, anagrelide, arsenic trioxide,asparaginase, axitinib, bexarotene, bevacizumab, bortezomib, celecoxib,denileukin diftitox, estramustine, hydroxycarbamide, lapatinib,pazopanib, pentostatin, masoprocol, mitotane, pegaspargase, tamoxifen,sorafenib, sunitinib, vemurafinib, vandetanib, and tretinoin. In oneexample, the disclosed compounds are used in combination with a biologicfor treating cancer (e.g., an antibody, such as a humanized antibody,which can be polyclonal, monoclonal, or chimeric, for examplealemtuzumab, bevacizumab, cetuximab, gemtuzumab, rituximab, panitumumab,pertuzumab, or trastuzumab).

Orally effective hypoglycemic active ingredients that can be used incombination with one or more of the disclosed compounds include, forexample, sulfonylureas, biguanides, meglitinides, oxadiazolidinediones,thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1agonists, DPP-IV inhibitors, potassium channel openers, insulinsensitizers, inhibitors of liver enzymes involved in the stimulation ofgluconeogenesis and/or glycogenolysis, modulators of glucose uptake,compounds which alter lipid metabolism and lead to a change in the bloodlipid composition, compounds which reduce food intake, and activeingredients which act on the ATP-dependent potassium channel of the betacells.

In certain embodiments, disclosed compounds are administered incombination with substances which influence hepatic glucose productionsuch as, for example, glycogen phosphorylase inhibitors; administered incombination with a biguanide such as, for example, metformin;administered in combination with a DPPIV inhibitor, such as(1-cyclopentyl-3-methyl-1-oxo-2-pentanammonium chloride), P-31/98,LAF237(1-[2-[3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2-(S)-carbonitrile),TS021((2S,4S)-4-fluoro-1-[[(2-hydroxy-1,1-dimethylethyl)amino]-acetyl]pyrrolidine-2-carbonitrilemonobenzenesulfonate); administered in combination with an α-glucosidaseinhibitor such as, for example, miglitol or acarbose; administered incombination with a bile acid reabsorption inhibitor; administered incombination with a polymeric bile acid adsorbent, such as, for example,cholestyramine or colesevelam; administered in combination with acholesterol absorption inhibitor, such as ezetimibe, tiqueside, orpamaqueside; administered in combination with an LDL receptor inducer;administered in combination with a mixed PPAR alpha/gamma agonist suchas, for example, Tesaglitazar,(S)-3-(4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl)-2-ethoxypropionicacid), or(N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine);administered in combination with a fibrate such as, for example,fenofibrate, gemfibrozil, clofibrate, bezafibrate; administered incombination with nicotinic acid or niacin; administered in combinationwith a CETP inhibitor, such as torcetrapib; administered in combinationwith an ACAT inhibitor; administered in combination with an MTPinhibitor such as, for example, implitapide; administered in combinationwith an antioxidant; administered in combination with a lipoproteinlipase inhibitor; administered in combination with an ATP citrate lyaseinhibitor; administered in combination with a squalene synthetaseinhibitor; administered in combination with fenfluramine ordexfenfluramine; administered in combination with sibutramine;administered in combination with leptin.

In one embodiment, disclosed compounds may be administered incombination with dexamphetamine, amphetamine, mazindole or phentermine;and administered in combination with medicaments having ananti-inflammatory effect.

B. Excipients and Dosage Forms

The present disclosure provides pharmaceutical compositions that includea prophylactically or therapeutically effective amount of one or moredisclosed compounds (such as 1, 2, 3, 4 or 5 disclosed compounds) inadmixture with at least one pharmaceutically acceptable material, suchas an excipient. Disclosed pharmaceutical compositions include adetectable amount of the PPAR agonist, such as greater than 0% to lessthan 100%, such as from 5% to 99%, or from about 50% to about 99%, orfrom 25% to about 99% by weight of the PPAR agonist of the presentdisclosure.

Disclosed compositions can be administered in any suitable dosage form,such as tablets, pills, capsules, powders, granules, sterile solutionsor suspensions, metered aerosol or liquid sprays, drops, ampoules,auto-injector devices or suppositories. The compositions are intendedfor any suitable administration route, including oral, parenteral,intranasal, sublingual, rectal, transdermal, inhalation or insufflation.The compositions may be formulated by methods known by those of ordinaryskill in the art, such as described in Remington's PharmaceuticalSciences (15th ed., Mack Publishing Company, Easton, Pa., 1980).

The compositions can be administered for therapeutic or prophylactictreatments. In therapeutic applications, compositions are administeredto a subject suffering from a disease (e.g., a PPARδ related disease) ina “therapeutically effective dose.” Amounts effective for this use candepend upon the severity of the disease and the general state of thesubject's health. Single or multiple administrations of the compositionscan be administered depending on the dosage and frequency as requiredand tolerated by the subject. Also, the composition, shape, and type ofdosage forms may vary depending on their use. For example, a dosage formused for acute treatment of a disease or disorder may contain largeramounts of the active ingredient than a dosage form used in the chronictreatment of the same disease or disorder. Similarly, a parenteraldosage form may contain smaller amounts of the active ingredient than anoral dosage form.

Oral dosage forms include, but are not limited to, tablets (includingwithout limitation scored or coated tablets), pills, granules, lozenges,caplets, capsules, chewable tablets, powder packets, cachets, troches,wafers, aerosol sprays, mucosal patches, or liquids, such as syrups,elixirs, solutions or suspensions in an aqueous liquid, for examplewater or saline, a non-aqueous liquid, an oil-in-water emulsion, or awater-in-oil emulsion. Typical oral dosage forms may be prepared bycombining the pharmaceutically acceptable PPAR agonist, potentially in aliquid, solid, granule or gelatin for and/or in a salt form, inadmixture with at least one excipient including, but are not limited to,surface stabilizers, dispersion aids, binders, filling agents,lubricating agents, glidants, suspending agents, sweeteners, flavoringagents, preservatives, buffers, wetting agents, disintegrants,effervescent agents, humectants, controlled release agents, absorptionaccelerators, absorbents, plasticizers, lactose, sucrose, mannitol,sorbitol, calcium phosphates, corn starch, potato starch, cellulose,hydroxy propyl methyl cellulose, microcrystalline cellulose, gelatin,acacia, sodium alginate, alginic acid, tragacanth, guar gum, gelatin,colloidal silicon dioxide, talc, magnesium stearate, stearic acid,colorants, diluents, talc, calcium carbonate, kaslin, maltodextrin,polymethacrylates, moistening agents, preservatives, dyes, and anycombination thereof.

Disintegrants facilitate producing tablets that disintegrate whenexposed to an aqueous environment. The amount of disintegrant usedvaries based upon the type of formulation and mode of administration,and is readily determined by a person of ordinary skill in the art.Typical pharmaceutical compositions comprise from about 0.5 to about 15weight percent of disintegrant, such as from about 1 to about 5 weightpercent of disintegrant. Disintegrants include, but are not limited to,agar-agar, alginic acid, guar gum, calcium carbonate, microcrystallinecellulose, croscarmellose sodium, carboxymethylcellulose calcium,methylcellulose, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, clays, other algins, other celluloses, gums, and mixturesthereof.

Exemplary lubricants include, but are not limited to, calcium stearate,magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol,mannitol, polyethylene glycol, other glycols, stearic acid, sodiumlauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil,cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), sodium benzoate, sodium stearylfumarate, zinc stearate,ethyl oleate, ethyl laureate, agar, syloid silica gel, synthetic silica,and mixtures thereof. Lubricants typically are used in an amount of lessthan about 1 weight percent of the pharmaceutical compositions.

Disclosed PPAR agonists, and related forms, such as salts, can beadministered as controlled- or delayed-release formulations.Controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledrelease counterparts. These dosage forms can be used to provide slow orcontrolled-release of one or more active ingredients using, for example,alginic acid, aliphatic polyesters, bentonite, cellulose acetate,phthalate, carnuba wax, chitosan, ethylcellulose, guar gum,microcrystalline wax, paraffin, polymethacrylates, povidone, xanthangum, yellow wax, carbomers, hydroxypropylcellulose, andhydroxypropylmethylcellulose.

Pharmaceutical compositions can also include large, slowly metabolizedmacromolecules such as proteins, polysaccharides, such as chitosan,polylactic acids, polyglycolic acids and copolymers (such as latexfunctionalized Sepharose™, agarose, cellulose, and the like), polymericamino acids, amino acid copolymers, and lipid aggregates (such as oildroplets or liposomes). Additionally, these carriers can function asimmunostimulating agents (i.e., adjuvants).

The compositions provided herein, alone or in combination with othersuitable components, can be made into aerosol formulations (e.g., theycan be “nebulized”) to be administered via inhalation. Aerosolformulations can be placed into pressurized acceptable propellants, suchas dichlorodifluoromethane, propane, nitrogen, and the like.

Suitable formulations for rectal administration include, for example,suppositories. Exemplary suppositories include a suppository base, suchas natural or synthetic triglycerides or paraffin hydrocarbons. Gelatinrectal capsules include a combination of the compound of choice with abase, including, for example, liquid triglycerides, polyethyleneglycols, and paraffin hydrocarbons.

Topical dosage forms include, but are not limited to, creams, lotions,ointments, gels, shampoos, sprays, aerosols, solutions, emulsions, andother forms know to a person of ordinary skill in the art. Suitableformulations include, without limitation, solutions, suspensions,emulsions, creams, ointments, powders, liniments, and salves.

Transdermal and mucosal dosage forms can include, but are not limitedto, ophthalmic solutions, patches, sprays, aerosols, creams, lotions,suppositories, ointments, gels, solutions, emulsions, or suspensions.Dosage forms suitable for treating mucosal tissues within the oralcavity can be formulated as mouthwashes, as oral gels, or as buccalpatches.

The disclosed PPAR agonists can be formulated for parenteraladministration, such as, for example, by intraarticular (in the joints),intravenous, intraarterial, intramuscular, intratumoral, intradermal,intraperitoneal, and subcutaneous routes. Examples of parenteral dosageforms include, but are not limited to, solutions ready for injection,dry products ready to be dissolved or suspended in a pharmaceuticallyacceptable vehicle for injection, suspensions ready for injection, andemulsions. In addition, controlled-release parenteral dosage forms canbe prepared. Suitable materials for such administration include sterilewater; saline solution; glucose solution; aqueous vehicles, such assodium chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose, Sodium Chloride Injection, Lactated Ringer's Injection; ethylalcohol, polyethylene glycol, and propylene glycol; non-aqueous vehiclessuch as, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate;aqueous and non-aqueous, isotonic sterile injection solutions, which cancontain antioxidants, buffers, bacteriostats, and solutes that renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions that can include suspendingagents, solubilizers, thickening agents, stabilizers, and preservatives.In the practice of this disclosure, compositions can be administered,for example, by intravenous infusion, orally, topically,intraperitoneally, intravesically or intrathecally. In an independentembodiment, parenteral administration, oral administration, and/orintravenous administration are the methods of administration. Theformulations of compounds can be presented in unit-dose or multi-dosesealed containers, such as ampules and vials.

The pharmaceutical preparation can be in unit dosage form. In such formthe preparation is subdivided into unit doses containing appropriatequantities of the active component. The unit dosage form can be apackaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The combined administrations contemplate coadministration, usingseparate formulations or a single pharmaceutical formulation, andconsecutive administration in either order, wherein, in someembodiments, there is a time period while both (or all) active agentssimultaneously exert their biological activities.

The particular mode of administration and the dosage regimen will beselected by the attending clinician, taking into account the particularsof the case (e.g. the subject, the disease, the disease state involved,the particular treatment, and whether the treatment is prophylactic).Treatment can involve daily or multi-daily or less than daily (such asweekly or monthly etc.) doses over a period of a few days to months, oreven years. For example, a therapeutically effective amount of one ormore compounds disclosed herein can be administered in a single dose,twice daily, weekly, or in several doses, for example daily such as two,three or four times daily, or during a course of treatment. Thedisclosed PPAR agonists may be administered substantially continuouslytoo, such as by using a transdermal delivery system. In a particularnon-limiting example, treatment involves once daily dose or twice dailydose. However, a person of ordinary skill in the art would immediatelyrecognize appropriate and/or equivalent doses looking at dosages ofapproved compositions for treating a PPARδ related disease using thedisclosed PPAR agonists for guidance.

The pharmaceutical compositions that include one or more compoundsdisclosed herein can be formulated in unit dosage form, suitable forindividual administration of precise dosages. In one non-limitingexample, a unit dosage contains from about 1 mg to about 50 g of one ormore compounds disclosed herein, such as about 10 mg to about 10 g,about 100 mg to about 10 g, about 100 mg to about 7 g, about 200 mg toabout 10 g, or about 200 mg to about 5 g. In other examples, atherapeutically effective amount of one or more compounds disclosedherein is from about 0.01 mg/kg to about 500 mg/kg, for example, about0.5 mg/kg to about 500 mg/kg, about 1 mg/kg to about 100 mg/kg, or about1 mg/kg to about 50 mg/kg. In other examples, a therapeuticallyeffective amount of one or more compounds disclosed herein is from about1 mg/kg to about 20 mg/kg, such as about 2 mg/kg to about 5 mg/kg. Insome embodiments, about 3 mg/kg or 10 mg/kg can be used.

V. Methods

Provided herein are methods of activating PPARδ.

Such methods can include contacting a PPARδ protein with an effectiveamount of a compound or composition provided herein, thereby activatingPPARδ. In some embodiments, the contacting is performed in vitro. Inother embodiments, the contacting is performed within a subject, such asa human subject, for example by administering a PPAR agonist disclosedherein to the subject. In some embodiments, the compound or compositionis administered ton a healthy subject. In some embodiments, the subjectis a sedentary or immobilized subject. In other embodiments, the subjectis an exercising subject, such as one who exercises for at least 20minutes, at least 30 minutes, at least 45 minutes, or at least 60minutes, at least 2, at least 3, or at least 4 days per week. In someembodiments, a healthy subject is also an exercising subject.

In some examples, contacting a PPARδ protein in vitro or in vivo with aneffective amount of one or more compounds or compositions providedherein, increases PPARδ activity by at least 10%, at least 20%, at least30%, at least 40%, at least 50%, at least 60%, at least 70%, at least80%, at least 90%, at least 95%, at least 100%, at least 200%, at least300%, at least 400%, or even at least 500%, for example as compared toan amount of PPARδ activity in the absence of the compound/composition.Methods of measuring PPARδ activity are known, and specific examples areprovided herein (e.g., measuring expression of PPARδ at the protein ornucleic acid level, measuring Beta oxidation levels, creatine kinaselevels, pentose phosphate shunt in liver, blood glucose levels andmethods provided in Wang et al., PLos Biol. 2(10):e294, 2004 and Lee etal., PNAS 103:3444-9, 2006).

In some embodiments, the subject recovers from acute injury followingadministration of the PPAR agonist.

In some embodiments, activating PPARδ within the subject byadministration of a PPAR agonist disclosed herein (or compositioncontaining the PPAR agonist) increases or maintains muscle mass ormuscle tone (such as a skeletal or cardiac muscle) in the subject (suchas in a healthy subject or a sedentary subject). For example, activatingPPARδ within the subject can increase muscle mass, muscle tone, or both,in the subject. In some examples, administering an effective amount ofone or more PPAR agonist compounds or compositions provided hereinincreases muscle mass, muscle tone, or both, by at least 10%, at least20%, at least 30%, at least 40%, at least 50%, at least 60%, at least70%, at least 80%, at least 90%, at least 95%, at least 100%, at least200%, at least 300%, at least 400%, or even at least 500%, for exampleas compared to an amount of PPARδ activity in the absence of thecompound/composition. Methods of measuring muscle mass and muscle toneare known, and specific examples are provided herein (e.g., see methodsprovided in WO 2009/086526).

In other embodiments, activating PPARδ within the subject (such as ahealthy subject or a sedentary subject) maintains muscle mass, muscletone, or both, in the subject. In some examples, administering aneffective amount of one or more PPAR agonist compounds or compositionsprovided herein maintains muscle mass, muscle tone, or both, such thatthe amount of muscle mass, muscle tone or both, does not change by morethan 1%, for example no more than 2%, no more than 3%, no more than 4%,no more than 5%, no more than 6%, no more than 7%, no more than 8%, nomore than 9%, no more than 10%, or no more than 15%, for example ascompared to an amount of muscle mass, muscle tone, or both in theabsence of the compound/composition. Methods of measuring muscle massand muscle tone are known, and specific examples are provided herein(e.g., see methods provided in WO 2009/086526).

Thus, the disclosed PPAR agonists and compositions containing such canbe used to increase or maintain muscle mass or muscle tone (or both) ina subject. For example, the disclosed PPAR agonists and compositionscontaining such can be used to increase or maintain muscle mass ormuscle tone (or both) in a subject following an injury, following aperiod of immobilization (for example confinement to a bed orwheelchair) or immobilization of a body part (for example immobilizationof an appendage or joint due to a broken bone, joint replacement, tendontear, surgery, and the like), which events can result in a loss ofmuscle mass and/or muscle tone. The method includes administering to thesubject a therapeutically effective amount of one or more compoundsprovided herein. In some embodiments, the subject is a sedentary orimmobilized subject. In other embodiments, the subject is an exercisingsubject.

Methods of treating or preventing a PPARδ-related disease or conditionin a subject in need thereof are provided. The methods can includeadministering to the subject a therapeutically effective amount of oneor more compounds or compositions provided herein. In some embodiments,the PPARδ-related disease is a vascular disease (such as acardiovascular disease or any disease that would benefit from increasingvascularization in tissues exhibiting impaired or inadequate bloodflow). In other embodiments, the PPARδ-related disease is a musculardisease, such as a muscular dystrophy. Examples of muscular dystrophyinclude but are not limited to Duchenne muscular dystrophy, Beckermuscular dystrophy, limb-girdle muscular dystrophy, congenital musculardystrophy, facioscapulohumeral muscular dystrophy, myotonic musculardystrophy, oculopharyngeal muscular dystrophy, distal musculardystrophy, and Emery-Dreifuss muscular dystrophy. In some embodiments,the PPARδ-related disease or condition is a demyelinating disease, suchas multiple sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacherdisease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy,or Guillian-Barre syndrome.

In some embodiments, the PPARδ-related disease is a metabolic disease.Examples of metabolic diseases include but are not limited to obesity,hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia,hypercholesterolemia, dyslipidemia, Syndrome X, and Type II diabetesmellitus.

Other PPARδ-related diseases that can be treated or prevented with thedisclosed PPAR agonists (or compositions containing such compound),include but are not limited to one or more of the following diseases:(1) a muscle structure disorder, such as Bethlem myopathy, central coredisease, congenital fiber type disproportion, distal muscular dystrophy(MD), Duchenne & Becker MD, Emery-Dreifuss MD, facioscapulohumeral MD,hyaline body myopathy, limb-girdle MD, a muscle sodium channeldisorders, myotonic chondrodystrophy, myotonic dystrophy, myotubularmyopathy, nemaline body disease, oculopharyngeal MD, and stress urinaryincontinence; (2) a neuronal activation disorder, such as amyotrophiclateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barre syndrome,Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, nervelesion, peripheral neuropathy, spinal muscular atrophy, tardy ulnarnerve palsy, toxic myoneural disorder, (3) a muscle fatigue disordersuch as chronic fatigue syndrome, diabetes (type I or II), glycogenstorage disease, fibromyalgia, Friedreich's ataxia, intermittentclaudication, lipid storage myopathy, MELAS, mucopolysaccharidosis,Pompe disease, thyrotoxic myopathy, (4) a muscle mass disorder such as,cachexia, cartilage degeneration, cerebral palsy, compartment syndrome,critical illness myopathy, inclusion body myositis, muscular atrophy(disuse), sarcopenia, steroid myopathy, and systemic lupuserythematosus, (5) a mitochondrial disease such as, Alpers's Disease,CPEO-Chronic progressive external ophthalmoplegia, Kearns-Sayra Syndrome(KSS), Leber Hereditary Optic Neuropathy (LHON), MELAS-Mitochondrialmyopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes,MERRF-Myoclonic epilepsy and ragged-red fiber disease, NARP-neurogenicmuscle weakness, ataxia, and retinitis pigmentosa, and Pearson Syndrome,(6) a beta oxidation disease such as, systemic carnitine transporter,carnitine palmitoyltransferase (CPT) II deficiency, very long—chainacyl—CoA dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzymedeficiency, medium—chain acyl—CoA dehydrogenase (MCAD) deficiency,short—chain acyl—CoA dehydrogenase (SCAD) deficiency,riboflavin—responsive disorders of 3-oxidation (RR-MADD), (7) ametabolic disease such as, hyperlipidemia, dyslipidemia,hyperchlolesterolemia, hypertriglyceridemia, HDL hypocholesterolemia,LDL hypercholesterolemia and/or HLD non-cholesterolemia, VLDLhyperproteinemia, dyslipoproteinemia, apolipoprotein A-Ihypoproteinemia, atherosclerosis, disease of arterial sclerosis, diseaseof cardiovascular systems, cerebrovascular disease, peripheralcirculatory disease, metabolic syndrome, syndrome X, obesity, diabetes(type I or II), hyperglycemia, insulin resistance, impaired glucosetolerance, hyperinsulinism, diabetic complication, cardiacinsufficiency, cardiac infarction, cardiomyopathy, hypertension,non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis(NASH), thrombus, Alzheimer disease, neurodegenerative disease,demyelinating disease, multiple sclerosis, adrenal leukodystrophy,dermatitis, psoriasis, acne, skin aging, trichosis, inflammation,arthritis, asthma, hypersensitive intestine syndrome, ulcerativecolitis, Crohn's disease, and pancreatitis, (8) a cancer such as, cancerof the colon, large intestine, skin, breast, prostate, ovary, or lung;(9) a vascular disease such as peripheral vascular insufficiency,peripheral vascular disease, intermittent claudication, peripheralvascular disease (PVD), peripheral artery disease (PAD), peripheralartery occlusive disease (PAOD), and peripheral obliterativearteriopathy; (10) an ocular vascular disease such as, age-relatedmacular degeneration (AMD), stargardt disease, hypertensive retinopathy,diabetic retinopathy, retinopathy, macular degeneration, retinalhaemorrhage, or glaucoma; or (11) a muscular eye disease such as,strabismus (crossed eye/wandering eye/walleye ophthalmoparesis),progressive external ophthalmoplegia, esotropia, exotropia, a disorderof refraction and accommodation, hypermetropia, myopia, astigmatism,anisometropia, presbyopia, a disorders of accommodation, or internalophthalmoplegia. Thus, in some examples, the subject treated has or isat risk for developing one or more of these diseases.

VI. Working Examples

Skeletal muscle relies on the resident progenitor cells, the satellitecells, for postnatal growth and regeneration. Therefore, maintaining anadequate number and proper function of satellite cells is critical formuscle to appropriately response to damage. While endurance exercisepromotes adaptive responses in the muscle, including an increase in thesatellite cell number, it is not known whether transcriptionallydirected “endurance exercise training” has similar effects. Here it isshown that mice harboring constitutively active PPARδ in skeletal muscledisplayed an accelerated regenerative process in muscle after an acuteinjury. Gene expression analyses showed earlier resolution of theinflammatory response and induction of myogenic markers, indicating thatPPARδ activation induces a temporal shift in the regenerative process.Notably, a significant increase in the number of satellite cells wasfound in mice with constitutively active PPARδ expressed in skeletalmuscle, consistent with the observed increase in proliferating cellnumber after the injury. PPARδ activation induced the expression ofFGF1, which is known to be involved in muscle development andregeneration. In particular, PPARδ up-regulates FGF1a isoform, which maybe responsible for supporting cell proliferation and reestablishment ofvasculature to augment the regenerative process. Furthermore, therestoration of fiber integrity was improved in wild-type mice afteracute treatment with the PPARδ synthetic ligand, GW501516. Collectively,these findings allude to the therapeutic potential of PPARδ, toaccelerate the recovery from acute muscle injury.

Activation of peroxisome proliferator activated receptor 6 (PPARδ)induces a fiber type switch toward a more oxidative phenotype, alteringboth metabolic and functional output of the muscle (Wang et al., PLoSBiol 2(10):e294. Erratum in: PLoS Biol. 2005 January; 3(1):e61 (2004);Luquet et al., FASEB J 17(15):2299-2301 (2003)). Specifically,PPARδ-mediated muscle remodeling translates into supernatural physicalendurance, and protection against diet-induced obesity and symptoms ofmetabolic disorders that ensue (Wang et al., PLoS Biol 2(10):e294.Erratum in: PLoS Biol. 2005 January; 3(1):e61 (2004); Wang et al., Cell113:159-170 (2003)). Furthermore, pharmacological activation of PPARδand exercise training synergistically enhance oxidative fibers andrunning endurance (Narkar V A et al., Cell 134(3):405-415 (2008)).Exercise confers a myriad of healthful benefits to the body, includingimprovement of atrophic and disease conditions (Nicastro et al., Braz JMed Biol Res 44(11):1070-9 (2011); Markert et al., Muscle Nerve43(4):464-78 (2011)). Recently, endurance exercise alone has been shownto improve ageing induced decrease in satellite cell number and theirmyogenic capacity (Shefer et al., PLoS One 5(10):e13307 (2010)).

It is demonstrated herein that both genetic and pharmacologicalactivation of PPARδ promote muscle regeneration in an acute thermalinjury mouse model. PPARδ activation during regeneration expeditesresolution of inflammatory response and restoration of contractileproteins. Interestingly, acute pharmacological activation of PPARδ byoral administration of a synthetic ligand, GW501516, is sufficient toconfer similar benefits during muscle regeneration after an acuteinjury. Based on these observations, a novel role of PPARδ during adultmuscle regeneration and its use as a therapeutic target to enhanceregenerative efficiency of skeletal muscle is provided.

Example 1 Experimental Procedures

A. Animals

VP16-PPARδ mice (Wang et al., Cell 113:159-170 (2003)) were bred toCB6F1 strain (Jackson Laboratories) and used as heterozygotes inexperiments. The non-transgenic littermates served as controls. Allexperiments were performed when animals were 8 weeks of age. Nestin-GFPmice (Mignone et al., J Comp Neurol 469(3):311-324 (2004)) were kindlyprovided by Dr. Fred Gage at the Salk Institute for Biological Studies.

B. Freeze burn injury

TA muscles were injured according to previously published methods with afew modifications (Brack et al., Science 317(5839):807-810 (2007)). Astainless steel Ig weight (Mettler-Toledo) equilibrated to thetemperature of dry ice was placed directly on the exposed TA for 10seconds. Following the thermal injury, incision was closed using VetBond(3M). All injury procedures were performed on the left leg, and theright leg was used as control.

C. Histology

Animals were perfused with 15 mL of ice-cold PBS followed immediately by20 mL of 10% saline buffered formalin. TA muscles were excised andimmersed in 4% paraformaldehyde for at least 48 hours at 4 OC. Tissueswere dehydrated in series of solutions with increasing percentage ofethanol. Dehydrated tissues were cleared in xylene and allowed forparaffin to permeate over night at 60° C. Tissues were then embedded inplastic molds.

Paraffin embedded tissue blocks were sectioned at 7 m thick on LeicaJung 2500 Microtome. Sections were stained with hematoxylin and counterstained with 1% eosin. Slides were dried and mounted with Entellanmounting media (EMS). Three random non-overlapping fields werephotographed for analysis. Regenerating fiber number was measured bycounting the number of discernible muscle fibers with centralizedmyonuclei (Ge et al., Am J Physiol Cell Physiol 297(6):C1434-1444(2009)). Regenerating fiber cross sectional area (CSA) was measuredusing Image J software.

D. Evans Blue dye staining

Injured animals were injected with Evans Blue dye according publishedprotocol (Hamer et al., J Anat 200(Pt 1):69-79 (2002)). Sterile 1% w/vEvans Blue dye in PBS was intraperitoneally injected at 1% volumerelative to the body mass of an animal. 7 hours after the injection,injured TA muscles were harvested and snap-frozen by isopentanequenching in liquid nitrogen. Frozen sections were cut in 10 μmthickness, fixed in ice-cold acetone, dipped in xylene and mounted withDPX. Proportion of the stained area over the total area was measuredusing ImageJ software.

E. BrdU Labeling

50 mg/kg body weight of BrdU (Sigma) was injected intraperitoneally assolution of 10 mg/mL BrdU in saline. TA muscles were harvested at 7 daysafter injury and processed for paraffin sections as described above.BrdU incorporation was visualized using the BrdU Labeling and DetectionKit I (Roche) and BrdU+ nuclei were counted and represented as aproportion of total nuclei in a field.

F. RT-QPCR

Whole or partial tissues were homogenized by Polytron probe homogenizerin Trizol reagent (Invitrogen). Total RNA was extracted from thehomogenates according to the manufacturer's protocol. 1 μg ofDNase-treated total RNA was reverse transcribed using Superscript IIReverse Transcriptase (Invitrogen) according to the manufacturer'sinstructions. cDNAs were diluted 1/40 with ddH₂O and used as templatesin RT-QPCR reactions with SYBRGreenER qPCR SuperMix detection system(Invitrogen). Samples were prepared in technical triplicates andrelative mRNA levels were calculated by using the standard curvemethodology and normalized against GAPDH mRNA levels in the samesamples.

G. Myofiber Isolation

Either whole or partial gastrocnemius muscle was digested in 2%collagenase I (Sigma) in DMEM with 10% FBS for 60 minutes at 37° C.Muscle tissue was further mechanically digested by triturating with firepolished wide bore Pasteur pipet. Liberated fibers were washed in twochanges of PBS with 10% FBS and finally mounted on glass slides withVectashield mounting media (Vector Labs).

H. Isolation of Satellite Cells

Satellite cells were harvested from TA of 8 weeks old animals accordingto published protocols with some modifications (Day et al. (2007)Nestin-GFP reporter expression defines the quiescent state of skeletalmuscle satellite cells. Dev Biol 304(1):246-259). Muscles were removedand washed briefly in DMEM on ice. They were then minced to fine slurrywith razor blade on 60 mm culture dish over ice. Minced muscles weretransferred to one well of a 6-well plate containing 5 ml of 450KPU/mlpronase in DMEM. The tissues were digested at 37° C./5% CO₂ for 60minutes. After digestion, tissues were vigorously triturated 20 timesthrough 10 ml serological pipet. Digested tissues were filtered through40 micron cell strainer and washed with equal volume of DMEM with 20%horse serum. Cells were spun down at 1000 g for 10 minutes andresuspended in sorting buffer (DMEM with 10% FBS). Cells were separatedfrom larger debris by 20%/60% Percoll gradient (Yablonka-Reuveni Z etal. (1987) Isolation and clonal analysis of satellite cells from chickenpectoralis muscle. Dev Bio 119: 252-259). GFP positive cells were sortedon BD FACSAria II sorter.

Example 2 Muscle Specific Activation of PPARδ Confers RegenerativeAdvantage

While it has been shown that the majority of the metabolic genes aredown regulated in this model, PPARδ expression was induced over 2 foldat 2 days after the injury (Warren et al. (2007) Mechanisms of skeletalmuscle injury and repair revealed by gene expression studies in mousemodels. J Physiol. 582.2: 825-841, FIG. 1A). This injury dependentup-regulation of PPARδ strongly suggested a possible role for PPARδduring the early part of the regenerative process.

Freeze burn injury was used to elicit the regenerative program, whichhas been shown to model the standard course of regenerative response,including satellite cell activation (Karpati and Molnar. “Muscle fibreregeneration in human skeletal muscle diseases.” In: Schiaffino S,Partridge T (eds). Skeletal muscle repair and regeneration. Springer,Dordrecht, 2008). Additionally, since the injury is directly applied tothe surface of the muscle, it is highly localized and reproducible.

Using Evans Blue dye uptake as a marker of myofiber damage, fiberintegrity was histologically assessed. The freeze burn injury does notincapacitate the animals and the damaged fibers restore original crosssectional area by 21 days after the injury (FIG. 1B).

By comparing the proportion of stained fibers within the cross sectionalarea (CSA) of the injured muscle 5 days after the injury, the degree ofexisting damage was quantified. At 5 days after the injury, VP16-PPARδ(TG) animals show significantly less dye uptake, thus increased fiberintactness, over the wildtype (WT) animals (FIG.>1C). While 14% of thetotal CSA shows dye uptake, only 5% of the total CSA of TG muscle showdye uptake (n=8 WT; n=5 TG; p=0.001) (FIG. 1D). At 12 and 36 hours afterthe injury, however, both WT and TG animals showed similar proportionsof stained area (50.6% and 47.4% (p=0.67), and 38.5% and 43.3% (p=0.23),respectively) (FIGS. 1E and 1F). Similar level of dye uptake shortlyafter the injury shows that both WT and TG animals initially sustainsimilar degree of damage from the injury and suggests that PPARδactivation does not confer protection from damage. Instead, thereduction in Evans Blue dye uptake observed 5 days after the injurysuggests that the muscle specific PPARδ activation promotes restorationof fiber integrity after the injury.

The morphological hallmarks of regenerating fibers was determined for adetailed analysis of the process. H&E stained transverse sectionsthrough the injured area were examined at 3, 5 and 7 days post injury.At 3 days after the injury, both WT and TG animals showed similardegrees of degeneration defined as necrosing fibers surrounded byinfiltrating monocytes (FIG. 1G). No regenerating fibers, characterizedby small, round shape and centralized nuclei, were discernible at thistime point in WT animals, but a notable few were seen in TG animals(arrows, FIG. 1G). By day 5 after the injury, obvious differences beginto emerge. In WT animals, small regenerating fibers were visible butnecrosing fibers and monocytes were still prevalent at the site of theinjury (arrowheads, FIG. 1G). While in the TG animals, the injury siteharbors orderly arrangement of small regenerating fibers. Quantificationof regenerating fiber number and CSA reveals that by 5 days post injury,TG animals show significant regenerative advantage over their WTcounterparts. Both CSA of the regenerating fibers and the number ofregenerating fibers were significantly greater for TG animals at 43.5%(n=5 or 6; p<0.03) and 33.0% (n=11 or 12; p<0.001), respectively (FIGS.1B and 1C). By day 7 post injury, the damage site appearsarchitecturally similar between WT and TG animals, where both show afield of immature regenerating fibers without the infiltrating immunecells. However, quantification of the regenerating fibers revealed aregenerative advantage of the TG animals in the number of nascentregenerating fibers (FIG. 1H). At 21 days after the injury, both WT andTG animals have restored their fiber size and number to that of theuninjured level (FIG. 1J). These data demonstrate that the musclespecific activation of PPARδ sufficiently bestows regenerativeadvantage, most prominently observed in the early stages of theregenerative process.

Example 3 PPARδ Activation Leads to Temporal Shift, Thus IncreasedEfficiency, of the Regenerative Process

Skeletal muscle regeneration is an intricately orchestrated processinvolving a variety of cell types. For example, immune cells, bothneutrophils and macrophages, are necessary for the proper progression ofregenerative process (Zacks et al., Muscle Nerve 5:152-161 (1982);Grounds et al., Cell Tissue Res 250:563-569 (1987); Teixeira et al.,Muscle Nerve 28(4):449-459 (2003); Summan et al., Am J Physiol RegulIntegr Comp Physiol 290:R1488-R1495 (2006); Contreras-Shannon et al., AmJ Physiol Cell Physiol 292:C953-967 (2007); Segawa et al., Exp Cell Res314(17):3232-3244 (2008)). Additionally, various cytokines are necessaryto promote chemotaxis of monocytes and also to directly regulate theactivities of myogenic cells (Warren et al., Am J Physiol Cell Physiol286(5):C1031-1036 (2004); Yahiaoui et al., J Physiol 586:3991-4004(2008); Chazaud et al., JCB 163(5):1133-1143 (2003)). Therefore, thetemporal expression profiles of genes associated with various aspects ofthe regenerative process was determined.

Global, injury specific gene expression changes, were identified inVP16-PPARδ animals by microarray. Comparing the gene expression profilesof injured TG to WT 3 days post-injury, 3257 genes that changedexpression pattern, of those, 1375 of them were down regulated and 1882were up regulated. Interestingly, genes involved in myogenesis andremodeling were robustly up-regulated by PPARδ activation while thoseinvolved in inflammatory response were down regulated in injured TGmuscles (FIG. 2A). Additionally, genes involved in developmentalprocesses, angiogenesis and anti-apoptotic processes emerged from theanalysis (FIG. 2A). Relative expressions of regeneration markers revealdown-regulation of early makers (inflammatory genes) and up-regulationof regenerative/remodeling genes (myogenic, vascularization, ECM genes)in TG animals 3 days post injury (FIG. 2B). Collectively, PPARδactivation appears to control a network of genes involved directly inmyogenesis and also in remodeling and repair processes after the injury.

Underlying phasic progression of the regenerative program is atemporally coordinated gene expression of a variety of contributingprocesses. In order to validate and temporally expand the microarraydata, expression of CD68 (inflammation) and MyoD (myogenesis) weremeasured by Q-PCR at several time points over 7 days after injury (FIGS.2C and 2D). A temporal shift in the expression patterns of regenerativemarkers for TG animals compared to their WT littermates was observed. TGanimals showed rapid induction of CD68 whose expressions peaked soonerand were subsequently down regulated earlier than in the WT animals.Interestingly, inflammatory markers studied here peaked at similarlevels between the two genotypes, which indicates that TG animals do notcompletely suppress their inflammatory responses. Instead, it appearsthat the TG animals respond and resolve their inflammatory responsesmore efficiently, which is consistent with the accelerated restorationof muscle morphology observed. TG animals also show higher expression ofperinatal myosin heavy chain gene, Myh8, at 7 days post injury,indicating more efficient reassembly of the contractile properties (FIG.2E). PPARδ activation leads to a temporal shift in the expressionpatterns of regenerative markers, which together with the histologydata, shows a role of PPARδ in increasing regenerative efficiency.

Example 4 PPARδ Directs Neo-Vascularization Via Regulation of FGF1

This example describes adaptive responses bestowed by PPARδ activationin the muscle which may contribute to the observed beneficial effects onregeneration.

Increased vasculature is one of the hallmarks of oxidative myofibers,which facilitates introduction of immune cells and also supportsincreased number of satellite cells. TG animals show increasedexpression of FGF1 in TA muscle (FIG. 3D). Upon injury, TG animalsmaintain high expression of FGF1 expression (FIG. 3D). Immunostainingtransverse sections of uninjured TA from WT and TG animals revealed 36%increase in the number of CD31+ capillaries per field by PPARδactivation (FIGS. 3A-C). Furthermore, after the injury, TG animals showincreased expression of CD31, which is indicative of increasedvascularity (FIG. 3E-F). The induction of FGF1a upon activation of PPARdelta with the GW1516 ligand was confirmed using a luciferase reporterassay (FIG. 3G). FGF1 has been shown to be expressed in regeneratingfibers in chronic disease models and has been implicated in myogenesisand regeneration (Oliver, Growth Factors. 1992; 7(2):97-106, 1992;Saito, 2000, Muscle Nerve. 23(4):490-7) and to increase microvasculaturein adipocytes and PPARδ directly regulates expression of FGF1a isoform(Jonker, et al., Nature. 485(7398):391-4, 2012). Therefore, increasedvascularity may contribute to the accelerated regenerative processobserved in VP16-PPARδ animals.

Example 5 PPARδ Activation Positively Regulates Quiescent Satellite CellNumber

One of the first events following the injury is the proliferation ofmuscle resident progenitors, the satellite cells. This example describesresults showing that the regenerative advantage observed in TG animalscould be due to altered satellite cell homeostasis.

Nestin expression was used as a marker of satellite cells, andnestin-GFP; VP16-PPARδ double transgenic animals were used togenetically label quiescent satellite cells(SCs) in vivo (Mignone etal., J Comp Neurol 469(3):311-324 (2004); Day et al., Dev Biol304(1):246-259 (2007)). Gastrocnemius muscles were enzymaticallydigested to liberate individual fibers, then mounted for quantification(FIG. 4A). While double transgenic animals averaged 1.01 SCs per mm offiber length, GFP+ animals only had 0.15 SCs per mm, a 6.48 fold higherSC content on VP16-PPARδ muscle fiber (FIG. 4B).

Satellite cell activity was measured as myoblast proliferation elicitedby the freeze burn injury in vivo. After the freeze burn injury, BrdUwas intraperitoneally injected at 12 hrs, 24 hrs and 2 days after theinjury and the muscles were harvested 7 days after the injury tocalculate the ratio of BrdU+ to total nuclei. TG animals showed 40-60%increase in the number of BrdU+ proliferating cells at all threeinjection times (FIG. 4C). Therefore, PPARδ induced increase in thenumber of quiescent satellite cells yields higher number of fusioncompetent myoblasts, leading to the enhancement of regenerative capacityof the muscle.

Example 6 Acute Pharmacological Activation of PPARδ Confers RegenerativeAdvantage

Pharmacological activation of PPARδ has been shown to induce PPARδtarget genes in fast-twitch hind limb muscles (Narkar et al., Cell134(3):405-415 (2008)). To demonstrate that an acute pharmacologicalactivation of PPARδ can modulate regenerative process after injury,C57BL6J mice were treated with GW501516 (Sundai Chemicals, China) orallyat 5 mg/kg for 4 days prior to and 5 days after the thermal injury tothe TA.

Up-regulation of known PPARδ target genes (PDK4, CPT1b, and catalase)was confirmed by QPCR, attesting to the successful delivery and activityof the PPARδ ligand in the muscle (FIG. 5A). While vehicle treatedanimals showed dye uptake in 7.6% of the cross sectional area (CSA),merely 4.9% of the muscle CSA was stained in the ligand treated animals(FIGS. 5B and 5C). Therefore, the drug treated animals showed 34.7%reduction in the proportion of stained area 5 days after the injury,demonstrating that pharmacological activation of PPARδ enablesaccelerated restoration of myofiber integrity after the injury.

Moreover, BrdU injection at 48 hours after the injury revealed thatPPARδ activation promotes myoblast proliferation after the injury (FIG.5D). However, an increase in the number of quiescent satellite cells wasnot observed after 9 days or 4 weeks of ligand treatment. Sincesatellite cells do not undergo rapid turnover, length of ligandtreatment may have been too short. Nonetheless, GW501516 treatmentpromoted myoblast proliferation in vivo after the injury, which maycontribute to the accelerated regeneration after the injury.

The expression of inflammatory marker genes at 3 days after the injurywas measured by QPCR. While the initial inflammatory responses aresimilarly generated with or without the PPARδ ligand treatment at 12hours after the injury, by 3 days after the injury, the expressions ofinflammatory marker genes were significantly reduced by the PPARδagonist treatment (FIG. 5E). This result is consistent with the knownrole of PPARδ as an anti-inflammatory, and also corroborates the datadiscussed earlier with the genetic over-expression of activated PPARδduring muscle regeneration.

In summary, PPARδ activation expedites skeletal muscle regenerationfollowing an acute thermal injury. VP16-PPARδ transgenic animals showedincreased satellite cell proliferation at the early phase of theregenerative process, which subsequently translated into increased CSAand the number of nascent regenerating fibers. Most interestingly,muscle specific over expression of PPARδ seems to increase the residentsatellite cell pool. Increased satellite cell population on a musclefiber seems to contribute to the accelerated resolution of the injury.These findings unveil a novel role for PPARδ in the maintenance ofskeletal muscle; as a potential therapeutic target for acceleratedrestoration of muscle mass after an acute injury and other atrophicconditions.

Notably, PPARδ activation seems to promote rapid emergence of nascentfibers after the injury. There being no evidence of hyperplasia at 21days after the injury when the regenerative process is essentiallycomplete, it is concluded that the additional nascent fibers efficientlyfuse with each other to restore mature fibers (Karpati G, Molnar M J inSkeletal muscle repair and regeneration, eds Schiaffino S, Partridge T(Springer, Dordrecht), (2008)). While IGF-1 and myostatin seem to relyon fiber hypertrophy to augment regenerative progress, PPARδ seems toemploy a unique way to promote regeneration (Menetrey et al., J BoneJoint Surg Br 82(1):131-7 (2000); Wagner et al., Ann Neurol 52(6): 832-6(2002); Bogdanovich et al., Nature 420(6914):418-21 (2002)). Underlyingthis difference may be the increased number of quiescent satellitecells. Higher number of progenitor cells leads to the increase in postinjury proliferating cells and consequent increase in the number ofnascent fibers. While various growth factors and chemokines, includingIGF-1 and myostatin, have been shown to enhance proliferation ofsatellite cells and promote regeneration, it is unclear whether any ofthem positively regulate the number of quiescent satellite cells(Husmann I et al., Cytokine Growth Factor Rev 7(3):249-258 (1996);McCroskery S et al., J Cell Biol 162(6):1135-1147 (2003); Musaro A etal., Nat Genet 27:195-200 (2001); Amthor H et al., PNAS 106(18):7479-84(2009)). The findings shown herein indicate a novel role of PPARδ as apositive regulator of satellite cell pool. Interestingly, since rapidcell proliferation was not observed under normal conditions, PPARδmediated satellite cell expansion is transient and tightly regulated,most likely elicited by external stimuli, such as signals for postnatalgrowth and injury. In an adult muscle, satellite cell number is finite,diminishing detrimentally in disease state and aging. It is of greattherapeutic benefit if PPARδ activation can bestow infinite abundance ofsatellite cell population throughout the life of an organism.

While enhancement in regenerative capacity was observed in both geneticand pharmacological models, the inherent differences in the experimentalparameters is acknowledged.

Orally administered GW501516 was delivered systemically, presumablyactivating PPARδ in a variety of organs and cell types in the animal.However, in VP16-PPARδ animals, activation of the PPARδ receptors islimited to the mature muscle fibers. Additionally, genetic background ofthe animals may affect the efficiency of regeneration after an injury(Grounds and McGeachie, Cell Tissue Res 255(2):385-391 (1989); Robertset al., J Anat 191:585-594 (1997)). Extramuscular effects of PPARδagonist administration may require further investigation whenconsidering clinical use of GW501516 to augment muscle injury treatment.Recently, pharmacological activation of PPARδ has been shown to improvesarcolemmal integrity in mdx mice (Miura et al., Hum Mol Genet18(23):4640-4649 (2009)).

The results herein expand previous understandings of the role of PPARδin muscle physiology. It is shown herein that PPARδ not only controlsrunning endurance and metabolic parameters in the muscle, but also itsregenerative program. PPARδ activation affects multiple facets of theregenerative program, exerting comprehensive but transient effects toexpedite the progress. In view of these findings, PPARδ may bepharmacologically targeted to enhance the regenerative capacity of themuscle after injury and possibly other degenerative conditions wheresatellite cell function is compromised. For example, PPARδ activationcan be used to treat other degenerative conditions such as aging inducedsatellite cell dysfunction and ensuing sarcopenia.

Example 7 PPARδ Activity Screen

Cell Culture and Transfection:

CV-1 cells were grown in DMEM+10% charcoal stripped FCS. Cells wereseeded into 384-well plates the day before transfection to give aconfluency of 50-80% at transfection. A total of 0.8 g DNA containing0.64 micrograms pCMX-PPARDelta LBD, 0.1 micrograms pCMX.beta.Gal, 0.08micrograms pGLMH2004 reporter and 0.02 micrograms pCMX empty vector wastransfected per well using FuGene transfection reagent according to themanufacturer's instructions (Roche). Cells were allowed to expressprotein for 48 h followed by addition of compound.

Plasmids:

Human PPARδ was used to PCR amplify the PPARδ LBD. The amplified cDNAligand binding domain (LBD) of PPARδ isoform was (PPARδ amino acid 128to C-terminus) and fused to the DNA binding domain (DBD) of the yeasttranscription factor GAL4 by subcloning fragments in frame into thevector pCMX GAL (Sadowski et al. (1992), Gene 118, 137) generating theplasmids pCMX-PPARDelta LBD. Ensuing fusions were verified bysequencing. The pCMXMH2004 luciferase reporter contains multiple copiesof the GAL4 DNA response element under a minimal eukaryotic promoter(Hollenberg and Evans, 1988). pCMXβGal was generated.

Compounds:

All compounds were dissolved in DMSO and diluted 1:1000 upon addition tothe cells. Compounds were tested in quadruple in concentrations rangingfrom 0.001 to 100 μM. Cells were treated with compound for 24 h followedby luciferase assay. Each compound was tested in at least two separateexperiments.

Luciferase Assay:

Medium including test compound was aspirated and washed with PBS. 50 μlPBS including 1 mM Mg++ and Ca++ were then added to each well. Theluciferase assay was performed using the LucLite kit according to themanufacturer's instructions (Packard Instruments). Light emission wasquantified by counting on a Perkin Elmer Envision reader. To measure3-galactosidase activity 25 μl supernatant from each transfection lysatewas transferred to a new 384 microplate. Beta-galactosidase assays wereperformed in the microwell plates using a kit from Promega and read in aPerkin Elmer Envision reader. The beta-galactosidase data were used tonormalize (transfection efficiency, cell growth etc.) the luciferasedata.

Statistical Methods:

The activity of a compound is calculated as fold induction compared toan untreated sample. For each compound the efficacy (maximal activity)is given as a relative activity compared to GW501516, a PPARδ agonist.The EC₅₀ is the concentration giving 50% of maximal observed activity.EC₅₀ values were calculated via non-linear regression using GraphPadPRISM (GraphPad Software, San Diego, Calif.).

Example 8 Synthetic Preparation of Compound Embodiments Abbreviations

rt room temperatureEDCI.HCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlorideHBTU O-benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphateHOBt 1-hydroxybenzotriazole

Reaction Step 1—Aryl Etherification

Material Source Mol. Wt. Density Equiv mmol Amount Ethyl-bromo-hexanoateSigma-Aldrich 223.12 1.258 1.0 10.0 1.77 mL SalicylaldehydeSigma-Aldrich 122.12 1.166 1.0 10.0 1.05 mL Cesium carbonateSigma-Aldrich 325.82 — 1.2 12.0 3.91 g DMA (solvent) Sigma-Aldrich — — —— 17.18 mL Ethyl 6-(2-formyl- Product 264.32 — (1.0) (10.0) (2.64 g)phenoxy)hexanoate

Reactions were carried out in a Biotage Initiator 60 Microwave Reactor,employing the 20 mL process-scale reactor vials. Thirteen (13) identicalreactions at the 10 mmol scale were setup in parallel and processed inserial, as follows:

All three (3) reagents and reaction solvent were added to the MW vial inthe following sequence; (1) ethyl-bromo-hexanoate (1.77 mL), (2)salicylaldehyde (1.05 mL), (3) cesium carbonate (Cs₂CO₃) (3.91 g) and(4) reaction solvent DMA (17.18 mL). Care was taken to dispense theN—N-dimethylacetamide (DMA) solvent in such a manner so as to wash downthe vial walls of reactant or solid base. To each vial was added amagnetic stir bar and fitted with a crimp seal cap and adapter collar.The reactions were than process in the MW Reactor for 10 minutes (attemperature) at 140° C. with mixing. Following standard ramp up, fixedhold time at temperature and cool down, samples were kept sealed atambient temperature until the entire lot was processed.

The reaction mixtures were combined and transferred to a 2 L separatoryfunnel. Vial contents were washed with ethyl acetate (EtOAc), and atotal EtOAc layer of about 800 mL was added. To this was added 800 mL of1.0 N NaOH solution, and the two layers were vigorously shaken and mixedand then separated. The NaOH aqueous layer was back-extracted 3×250 mLwith EtOAc, and all the organic layers were combined (about 750 mL) andwashed with 800 mL of 1.0 M citric acid solution. The citric acid layerwas again back extracted with EtOAc (3×250 mL), and the organic layerswere again combined (about 1.5 L) and washed (3×500 mL) with brine(saturated NaCl), dried over sodium sulfate (Na₂SO₄) and concentrated todryness in vacuo. Silica gel TLC (3:1 Hexanes-EtOAc) R_(f)=0.34(product), R_(f)=0.45, 0.25 (trace impurities). Theoreticalyield=13×2.64 g or 34.32 g (130 mmol). Isolation and Observedyield=33.30 g, (33.30 g/34.32 g×100)=97%. NMR (¹H, ¹³C, COSY) and LCMS(ESI+/−) conform to structure.

Reaction Step 2—Reductive Amination

Material Source Mol. Wt. Density Equiv. mmol Amount Ethyl 6-(2-formyl-Reaction1 264.32 — 1.0 10.0 2.6557 g phenoxy)hexanoate ProductCyclopropylamine Sigma-Aldrich 57.09 0.814 1.1 11.0 769 μL Acetic acid,gl. Sigma-Aldrich 60.04 1.04 6.6 66.0 3.81 mL NaBH(OAc)₃ Sigma-Aldrich211.94 — 2.2 22.0 4.67 g DCE (solvent) Sigma-Aldrich — — — — 10.0 mLEthyl 6-(2-((cyclo- Product 304.42 — (1.0) (10.0) (3.04 g)propylamino)methyl) phenoxy)hexanoate

Reactions were carried out in a Biotage Initiator 60 Microwave Reactor,employing the 20 mL process-scale reactor vials. Twelve (12) identicalreactions at the 10 mmol scale were setup in parallel and processed inserial, as follows:

All four (4) reagents and reaction solvent were added to the MW vial inthe following sequence; (1) Ethyl 6-(2-formylphenoxy)hexanoate (about2.66 g), (2) cyclopropylamine (769 μL), (3) acetic acid (AcOH) (3.81 mL)and 50% of the reaction solvent 1,2-dichloroethane (DCE), (4) sodiumtriacetoxyborohydride (4.67 g) and (5) the remaining 5 mL portion ofDCE. Care was taken to dispense the DCE solvent in such a manner so asto wash down the vial walls of reactant or solid reducing agent. To eachvial was added a magnetic stir bar and fitted with a crimp seal cap andadapter collar. The reactions were than process in the MW Reactor for 10minutes (at temperature) at 120° C. with mixing. Following standard rampup, fixed hold time at temperature and cool down, samples were keptsealed at ambient temperature until the entire lot was processed.

The reaction mixtures were combined and transferred to a 2 L separatoryfunnel. Vial contents were washed with ethyl acetate (EtOAc), and atotal EtOAc layer of about 1 L was added. To this was added 800 mL ofsaturated NaHCO₃ solution, and the two layers were vigorously shaken andmixed and then separated, this extraction was performed an additional 2times (3×800 mL in total). The organic EtOAc layer was then washed withbrine (1×800 mL). The combined bicarb and brine aqueous layers were thenback-extracted 1×200 mL with EtOAc, and all the organic layers werecombined (about 1.4 L) and dried over sodium sulfate (Na₂SO₄) andconcentrated to dryness in vacuo.

Observed crude yield=36.21 g of crude product. Three (3) spots by silicagel TLC (95:5 DCM-MeOH), R_(f)=0.17 (product), R_(f)=0.22 (tertiaryamine by-product), R_(f)=0.08 (unk). Purified by silica gelchromatography, Biotage SP4, 65i column with samplet cartridge. A totalof 3-columns were run, about 12 g of crude loaded into the samplet inMeOH and dried in vacuo. Elution program was as follows: 1 CV@99% DCM-1%MeOH, then 10 CV@gradient 99→90% DCM and 1-10% MeOH, and 2 CV@90%DCM-10% MeOH. Fractions were combined, concentrated and dried undervacuum. Theoretical yield=12×3.04 g or 36.53 g (120 mmol). Isolation andObserved yield=29.28 g, (29.28 g/36.53 g x 100)=80.2%. NMR (¹H, ¹³C,COSY) and LCMS (ESI+/−) conform to structure.

Reaction Step 3—Aryl Amide Formation

Material Source Mol. Wt. Density Equiv. Mmol Amount Ethyl 6-(2-((cyclo-Reaction2 304.42 — 1.0 4.42 1.35 g propylamino)methyl) Productphenoxy)hexanoate 4-bromo-benzoyl Lancaster 219.47 — 1.1 4.86 1.067 gchloride DIEA (Hunig's base) Sigma-Aldrich 129.25 0.742 2.2 9.72 933 μLDCE (solvent) Sigma-Aldrich — — — — 15.0 mL Ethyl 6-(2-((4-bromo-N-Product 488.41 — (1.0) (4.42) (2.16 g) cyclopropylbenzamido)methyl)phenoxy) hexanoate

Reactions were carried out in a Biotage Initiator 60 Microwave Reactor,employing the 20 mL process-scale reactor vials. Twenty (20) identicalreactions at the 4.42 mmol scale were setup in parallel and processed inserial, as follows:

All three (3) reagents and reaction solvent were added to the MW vial inthe following sequence; (1) Ethyl 6-(2-((cyclo-propylamino)methyl)phenoxy)hexanoate (about 1.35 g), (2) 4-bromobenzoyl chloride(4-BrBzCl)(1.067 g), (3) DIEA (933 μL), (3.81 mL) and 50% of thereaction solvent 1,2-dichloroethane (DCE), and (4) the remaining 7.5 mLportion of DCE. Care was taken to dispense the DCE solvent in such amanner so as to wash down the vial walls of solid 4-BrBzCl. To each vialwas added a magnetic stir bar and fitted with a crimp seal cap andadapter collar. The reactions were than process in the MW Reactor for 10minutes (at temperature) at 75° C. with mixing. Following standard rampup, fixed hold time at temperature and cool down, samples were keptsealed at ambient temperature until the entire lot was processed.

The reaction mixtures were combined and transferred to a 2 L separatoryfunnel. Vial contents were washed with ethyl acetate (EtOAc), and atotal EtOAc layer of about 1 L was added. To this was added 800 mL ofsaturated NaHCO₃ solution, and the two layers were vigorously shaken andmixed and then separated, this extraction was performed one additionaltime (2×800 mL in total). The organic EtOAc layer was then washed withbrine (2×800 mL). The combined bicarb and brine aqueous layers were thenback-extracted 1×200 mL with EtOAc, and all the organic layers werecombined (about 1.4 L) and dried over sodium sulfate (Na₂SO₄) andconcentrated to dryness in vacuo.

Observed crude yield=45.3 g of crude product which was an oilysemi-solid. Three (3) spots by silica gel TLC (2:1 Hexanes-EtOAc),R_(f)=0.42 (product), R_(f)=0.50, 0.17 (by-products). Purified by silicagel chromatography, Biotage SP4, 65i column with samplet cartridge. Atotal of 4-columns were run, about 11 g of crude loaded into the sampletin MeOH and dried in vacuo. Elution program was as follows: 1 CV@92%Hex-8% EtOAc, then 10 CV@gradient 92-34% DCM and 8-66% EtOAc, and 2CV@34% Hex-66% EtOAc. Fractions were combined, concentrated and driedunder vacuum. Theoretical yield=20×2.16 g or 43.2 g (88.4 mmol).Isolation and Observed yield=23.02 g, (23.02 g/43.2 g x 100)=53.3%(yields ranging from 50-80% have been obtained depending on the batch of4-BrBzCl and the degree to which this reaction is carried out underanhydrous conditions). NMR (¹H, ¹³C, COSY) and LCMS (ESI+/−) conform tostructure.

Reaction Step 4—Suzuki Coupling

Material Source Mol. Wt. Density Equiv. mmol Amount Ethyl6-(2-((4-bromo-N- Reaction3 488.41 — 1.0 4.09 2.00 gcyclopropylbenzamido) Product methyl)phenoxy) hexanoate Furan-2-boronicacid Alfa Aesar 111.89 — 1.25 5.11 572 mg Pd(PPh₃)₄ Sigma-Aldrich1155.58 — 0.03 0.123 141.8 mg 2.0M Na₂CO₃ aq. Sigma-Aldrich — — 3.0 12.36.135 mL DME (solvent) Sigma-Aldrich — — — — 4.6 mL EtOH, 95%(co-solvent) Sigma-Aldrich — — — — 4.6 mL Ethyl 6-(2-((N- Product 475.61— (1.0) (4.09) (1.95 g) cyclopropy1-4-(furan-2- yl)benzamido)methyl)phenoxy) hexanoate

Reactions were carried out in a Biotage Initiator 60 Microwave Reactor,employing the 20 mL process-scale reactor vials. Eleven (11) identicalreactions at the 4.09 mmol scale were setup in parallel and processed inserial, as follows:

All four (4) reagents and reaction co-solvents were added to the MW vialin the following sequence; (1) Ethyl6-(2-((4-bromo-N-cyclopropylbenzamido)methyl)phenoxy) hexanoate (about 2g), (2) Furan-2-boronic acid (572 mg), (3) Pd(PPh₃)₄ (141.8 mg), (4) 2.0M sodium carbonate solution (6.135 mL), followed by the co-solvents 95%EtOH and DME (1,2-dimethoxyethane). Care was taken to dispense the DMEsolvent in such a manner so as to wash down the vial walls of solidcatalyst. To each vial was added a magnetic stir bar and fitted with acrimp seal cap and adapter collar. The reactions were than process inthe MW Reactor for 10 minutes (at temperature) at 140° C. with mixing.Following standard ramp up, fixed hold time at temperature and cooldown, samples were kept sealed at ambient temperature until the entirelot was processed. Note, depending on the age of the tetrakis Pdcatalyst (fresh when red, darkens to brown with age) the microwavereaction temperature may need to be increased and the reaction timelengthened. It has been observed that a trace side product increaseswith reaction temp/time and corresponds to the saponified ester, whichis the next and final synthetic step. This ester hydrolysis should beexpected given the excess base in the presence of water and ethanol asco-solvents. Therefore the ethyl ester is not isolate.

The crude reaction mixtures were individually opens and poured out ontoan 800 mL sintered filtration funnel (medium porosity) fitted with a 2 Lside arm Erlenmeyer flask attached to house vacuum. The funnel wascharged with a 2-3″ bed of flash grade silica gel (Silicycle, 60 Å,40-63 m, F60 silica gel). A second layer (about 1-2″) of diatomaceousearth filter aid (Celite 545) was packed on top of the silica gel, toproduce a binary dry column vacuum chromatography (DCVC) system. Atypical CV was about 100 mL, and each reaction mixture was eluted with1CV of chromatography grade THF. The column was washed with 4CV of THFuntil no reaction product(s) were visible by TLC. The THF mixture wasconcentrated to produce about 25 g of viscous oil isolated, that wasthen taken directly onto the next step. Theoretical yield=11×1.95 g or21.45 g (45.0 mmol). NMR (¹H, ¹³C, COSY) and LCMS (ESI+/−) conform tostructure.

Reaction Step 5—Saponification

Mol. Material Source Wt. Density Equiv. Mmol Amount Ethyl 6-(2-((N-Reaction4 475.61 — 1.0 2.045 972.4 mg cyclopropyl-4-(furan-2- Productyl)benzamido) methyl)phenoxy) hexanoate LiOH · H₂O Sigma-Aldrich 41.96 —4.89 10 420 mg THF (solvent) Sigma-Aldrich — — — — 15 mL H₂O(co-solvent) Sigma-Aldrich — — — — 5 mL 6-(2-((N-cyclopropyl-4- Product447.52 — (1.0) (2.045) (915.2 mg) (furan-2-yl)benzamido)methyl)phenoxy)hexanoic acid

Reactions were carried out in a Biotage Initiator 60 Microwave Reactor,employing the 20 mL process-scale reactor vials. Twenty-two (22)identical reactions at the 2.045 mmol scale were setup in parallel andprocessed in serial, as follows:

All two (2) reagents and reaction co-solvents were added to the MW vialin the following sequence; (1) crude ethyl6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy) hexanoatewas dissolved to a volume of 33 mL, 15 mL per reaction vial, and (2)LiOH (hydrate) as a 2 M solution in water, 5 mL per reaction vial. Toeach vial was added a magnetic stir bar and fitted with a crimp seal capand adapter collar. The reactions were than process in the MW Reactorfor 10 minutes (at temperature) at 150° C. with mixing. Followingstandard ramp up, fixed hold time at temperature and cool down, sampleswere kept sealed at ambient temperature until the entire lot wasprocessed.

The crude reaction mixtures were individually opens and poured out ontoan 800 mL sintered filtration funnel (medium porosity) fitted with a 2 Lside arm Erlenmeyer flask attached to house vacuum. The funnel wascharged with a 2-3″ bed of flash grade silica gel (Silicycle, 60 Å,40-63 μm, F60 silica gel). A second layer (about 1-2″) of diatomaceousearth filter aid (Celite 545) was packed on top of the silica gel, toproduce a binary dry column vacuum chromatography system. The dry columnwas acid washed (acidified with either 1M citric acid or 1N HCl) with2×1 L of acid solution. A typical CV was about 100 mL, and each reactionmixture was eluted with 1 CV of 1:1 DCM-THF. The column was washed with4 CV of 1:1 DCM-THF until no reaction product(s) were visible by TLC.The DCM-THF mixture was concentrated to produce about 21 g of viscousoil. This crude product exhibited impurities with R_(f) values close tothat of the desired material. Flash chromatography used four (4) Biotage65i columns on Biotage SP4, loading about 5 g crude. Theoreticalyield=22×915.2 mg or 20.13 g (45.0 mmol). Isolation and Observedyield=11.54 g, (11.54 g/20.13 g x 100)=57.3%. NMR (¹H, ¹³C, COSY) andLCMS (ESI+/−) conform to structure.

Reaction Step 6—Salt Formation

Mol. Material Source Wt. Density Equiv. mmol Amount6-(2-((N-cyclopropyl-4- Reaction5 447.52 -— 1.0 25.78 11.54 g(furan-2-yl)benzamido) Product methyl)phenoxy)hexanoic acid NaOH Sigma-40.00 — 1.1 28.36 1.135 g Aldrich THF (solvent) Sigma- — — — — 75 mLAldrich H₂O (co-solvent) Sigma- — — — — 25 mL Aldrich Sodium 6-(2-((N-Product 469.50 — (1.0) (25.78) (12.10 g) cyclopropyl-4-(furan-2-yl)benzamido) methyl)phenoxy) hexanoate

6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid was dissolved in 75 mL of THF and cooled to 0° C. NaOH (1.135 g)was dissolved in 25 mL water, and added dropwise to the stirring THFsolution. After the addition was complete the reaction color was verydark (grayish-black), the ice bath was removed and the reaction asallowed to warm to room temperature and continue to stir an additional 2hours. The crude reaction mixture was then concentrated and the waterwas azeotroped away by charging the flask with about 100 mL portions ofMeCN (20 times). The solution salt still was not crashing out orprecipitating, so the crude salt was places on high vacuum overnight. Awhite crystalline solid appeared, and was triturated with fresh portionsof MeCN, filtered and dried overnight once again to yield a 10.0 gportion (excluding additional material for secondary crystallizationfrom the mother liquor). Theoretical yield=12.1 g (25.78 mmol). Observedyield=10.0 g, (10.0 g/12.1 g x 100)=82.6%. NMR (¹H, ¹³C, COSY) and

TABLE 1 MW MW EC₅₀ ID Formula Calc. Obser. nM Structure  1 C₂₉H₃₃NO₄459.58 458.2 [M − H]−   42

 2 C₃₀H₃₉BrN₂O₅ 587.55 587.2/ 589.2 [M + H]+

 3 C₃₆H₄₄N₂O₅ 584.74 585.3 [M + H]+

 4 C₃₂H₃₆N₂O₅ 528.64 529.3 [M + H]+

 5 C₃₄H₄₀N₂O₅ 556.69 555.3 [M − H]−

 6 C₃₀H₃₂N₂O₅ 500.59 499.2 [M − H]−

 7 C₃₀H₃₃N₃O₅ 515.6 514.2 [M − H]−

 8 C₂₉H₃₁NO₄ 457.56 456.2 [M − H]−   115

 9 C₂₈H₃₀N₂O₄ 458.55 457.2 [M − H]−  1960

10 C₂₈H₃₀N₂O₄ 458.55 457.2 [M − H]−

11 C₂₆H₂₉N₃O₄ 447.53 446.2 [M − H]−  2120

12 C₂₇H₂₉NO₅ 447.52 466.2 [M − H]−   19.6

13 C₂₇H₂₉NO₅ 447.52 446.2 [M − H]−   215

14 C₂₇H₂₉NO₄S 463.59 466.2 [M − H]−  1800

15 C₂₇H₂₉NO₄S 463.59 466.2 [M − H]−   58.4

16 C₃₃H₃₃NO₄ 507.62 506.2 [M − H]−

17 C₃₂H₃₂N₂O₄ 508.61 507.2 [M − H]−

18 C₃₂H₃₂N₂O₄ 508.61 507.2 [M − H]−

19 C₃₀H₃₁N₃O₄ 497.58 496.2 [M − H]−

20 C₃₁H₃₁NO₅ 497.58 496.2 [M − H]−

21 C₃₁H₃₁NO₅ 497.58 496.2 [M − H]−

22 C₃₁H₃₁NO₄S 513.65 512.2 [M − H]−

23 C₃₁H₃₁NO₄S 513.65 512.2 [M − H]−

24 C₃₃H₃₄N₂O₄ 522.63 521.2 [M − H]−

25 C₃₂H₃₃N₃O₄ 523.62 522.2 [M − H]−

26 C₃₂H₃₃N₃O₄ 523.62 522.2 [M − H]−

27 C₃₀H₃₂N₄O₅ 512.6 511.2 [M − H]−

28 C₃₁H₃₂N₂O₅ 512.6 511.2 [M − H]−

29 C₃₁H₃₂N₂O₅ 512.6 511.2 [M − H]−

30 C₃₁H₃₂N₂O₄S 528.66 527.2 [M − H]−

31 C₃₁H₃₂N₂O₄S 528.66 527.2 [M − H]−

32 C₂₄H₃₀BrNO₄ 476.4 476.1/ 474.1 [M − H]−   611

33 C₃₀H₃₅NO₄ 473.6 472.3 [M − H]−   954

34 C₂₉H₃₄N₂O₄ 474.59 473.2 [M − H]−  5140

35 C₂₉H₃₄N₂O₄ 474.59 473.2 [M − H]−  6400

36 C₂₇H₃₃N₃O₄ 463.57 462.2 [M − H]− 15400

37 C₂₈H₃₃NO₅ 463.57 462.2 [M − H]−   41

38 C₂₈H₃₃NO₅ 463.57 462.2 [M − H]−  290

39 C₂₈H₃₃NO₄S 479.63 478.2 [M − H]−  2100

40 C₂₈H₃₃NO₄S 479.63 478.2 [M − H]−  179

41 C₃₃H₄₀N₂O₅ 544.68 543.3 [M − H]−

42 C₃₂H₃₉N₃O₅ 545.67 544.3 [M − H]−

43 C₃₂H₃₉N₃O₅ 545.67 544.3 [M − H]−

44 C₃₀H₃₈N₄O₅ 534.65 533.3 [M − H]−

45 C₃₁H₃₈N₂O₆ 534.64 533.3 [M − H]−

46 C₃₁H₃₈N₂O₆ 534.64 533.3 [M − H]−

47 C₃₁H₃₈N₂O₅S 550.71 549.2 [M − H]−

48 C₃₁H₃₈N₂O₅S 550.71 549.2 [M − H]−

49 C₃₃H₃₄N₂O₄ 522.63 521.2 [M − H]−

50 C₃₂H₃₃N₃O₄ 523.62 522.2 [M − H]−

51 C₃₂H₃₃N₃O₄ 523.62 522.2 [M − H]−

52 C₃₀H₃₂N₄O₄ 512.6 511.2 [M − H]−

53 C₃₁H₃₂N₂O₅ 512.6 511.2 [M − H]−

54 C₃₁H₃₂N₂O₅ 512.6 511.2 [M − H]−

55 C₃₁H₃₂N₂O₄S 528.66 527.2 [M − H]−

56 C₃₁H₃₂N₂O₄S 528.66 527.2 [M − H]−

57 C₂₉H₃₃NO₄ 459.58 458.2 [M − H]−   60

58 C₂₈H₃₂N₂O₄ 460.56 459.2 [M − H]−  1240

59 C₂₈H₃₂N₂O₄ 460.56 459.2 [M − H]−  2860

60 C₂₆H₃₁N₃O₄ 449.54 448.2 [M − H]−   710

61 C₂₇H₃₁NO₅ 449.54 448.2 [M − H]−    9.0

62 C₂₇H₃₁NO₅ 449.54 448.2 [M − H]−   61

63 C₂₇H₃₁NO₄S 465.6 464.2 [M − H]− ND

64 C₂₇H₃₁NO₄S 465.6 464.2 [M − H]−   17.2

65 C₃₁H₃₅NO₄ 485.61 484.3 [M − H]−  405

66 C₃₀H₃₄N₂O₄ 486.6 485.2 [M − H]−  786

67 C₃₀H₃₄N₂O₄ 486.6 485.2 [M − H]−  1490

68 C₂₈H₃₃N₃O₄ 475.58 474.2 [M − H]−  605

69 C₂₉H₃₃NO₅ 475.58 474.2 [M − H]−   51.4

70 C₂₉H₃₃NO₅ 475.58 474.2 [M − H]−  127

71 C₂₉H₃₃NO₄S 491.64 490.2 [M − H]−  753

72 C₂₉H₃₃NO₄S 491.64 490.2 [M − H]−   29.3

73 C₃₃H₃₃NO₄ 507.62 506.2 [M − H]− ND

74 C₃₃H₃₃NO₄ 507.62 506.2 [M − H]− ND

75 C₃₀H₃₃NO₄ 471.59 470.2 [M − H]−  1190

76 C₃₀H₃₃NO₄ 471.59 470.2 [M − H]−  318

77 C₃₀H₃₃NO₄ 471.59 470.2 [M − H]−  372

78 C₃₀H₃₃NO₅ 487.59 486.2 [M − H]−  1870

79 C₃₀H₃₃NO₅ 487.59 486.2 [M − H]−  301

80 C₃₀H₃₃NO₅ 487.59 486.2 [M − H]−  439

81 C₂₉H₃₀FNO₄ 475.55 474.2 [M − H]−  597

82 C₂₉H₃₀FNO₄ 475.55 474.2 [M − H]−  150

83 C₂₉H₃₀FNO₄ 475.55 474.2 [M − H]−  364

84 C₃₁H₃₅NO₄ 485.61 484.3 [M − H]−  2500

85 C₃₁H₃₅NO₄ 485.61 484.3 [M − H]− ND

86 C₃₁H₃₅NO₄ 485.61 484.3 [M − H]−  1300

87 C₃₁H₃₅NO₄ 485.61 484.3 [M − H]−  1150

88 C₃₁H₃₅NO₄ 485.61 484.3 [M − H]− ND

89 C₃₁H₃₅NO₄ 485.61 484.3 [M − H]−  1760

90 C₃₀H₃₀F₃NO₄ 525.56 524.2/ 525.2 [M − H]−  1300

91 C₃₀H₃₀F₃NO₄ 525.56 524.2/ 525.2 [M − H]−  1150

92 C₃₀H₃₀F₃NO₄ 525.56 524.2/ 525.2 [M − H]−  1760

93 C₃₂H₃₇NO₄ 499.64 498.3 [M − H]−  1340

94 C₃₃H₃₉NO₄ 513.67 512.3 [M − H]− ND

95 C₃₅H₃₅NO₄ 533.66 532.3 [M − H]− ND

Example 1 Synthesis of6-(2-((6-(Furan-2-yl)-N-isopropylnicotinamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl 6-(2-formylphenoxy)hexanoate

A solution of salicylaldehyde (5.0 g, 40.9 mmol) in DMF (50 mL) wastreated with potassium carbonate (8.48 g, 61 mmol) and ethyl-6-bromohexanoate (10.96 g, 49.4 mmol) at rt under nitrogen atmosphere. Theresulting reaction mixture was heated at 80° C. with constant stirringfor 3 h. The reaction mixture was cooled to rt and filtered and washedwith ethyl acetate. The filtrate was concentrated under reduced pressureand residue obtained was diluted with cold water (50 mL), beforeextracting with ethyl acetate (200 mL). The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (elution, 10% EtOAc-hexanes) to afford the title compound(10.01 g, 93.4% yield). LCMS (m/z): 265.5 (M+1)⁺.

b) Synthesis of ethyl 6-(2-((isopropylamino)methyl)phenoxy)hexanoate

In a 100-mL round bottom flask, isopropyl amine (2.70 g, 45.7 mmol) andethyl 6-(2-formylphenoxy)hexanoate (10 g, 37.8 mmol) were dissolved in1,2-dichloroethane (50 mL) at rt. AcOH (14.8 mL) was added carefully tothe above mixture (exothermic) followed by portion wise addition ofsodium triacetoxyborohydride (17.8 g, 83.9 mmol) at rt. The reactionmixture was stirred at rt under nitrogen atmosphere for 4 h. Thereaction mixture was quenched by adding saturated sodium carbonatesolution, and was extracted with ethyl acetate. The ethyl acetateextract was washed with brine and dried over anhydrous Na₂SO₄. Thesolution was concentrated under reduced pressure to give title compound(11.1 g, 94%). LCMS (m/z): 308.5 (M+1)⁺.

c) Synthesis of ethyl6-(2-((6-chloro-N-isopropylnicotinamido)methyl)phenoxy) hexanoate

In a 50-mL round bottom flask, EDCI.HCl (0.746 g, 3.89 mmol) and DIPEA(1.3 mL, 7.46 mmol) were added to a solution of ethyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate (1.0 g, 3.25 mmol),6-chloronicotinic acid (0.612 g, 3.9 mmol) and HOBt (0.598 g, 3.9 mmol)in dimethylformamide (10 mL) at rt under nitrogen atmosphere. Thereaction mixture was stirred at rt for 16 h under nitrogen atmosphere.The reaction mixture was concentrated under reduced pressure and residueobtained was purified by silica gel column chromatography (eluting with10% EtOAc-hexanes) to furnish the title compound (1.2 g, 75.4%). LCMS(m/z): 469.1 (M+Na)⁺.

d) Synthesis of ethyl6-(2-((6-(furan-2-yl)-N-isopropylnicotinamido)methyl)phenoxy) hexanoate

In a 25-mL round bottom flask, a stirred solution of ethyl6-(2-((6-chloro-N-sopropylnicotinamido)methyl)phenoxy)hexanoate (1.2 g,2.69 mmol), furan-2-ylboronic acid (0.328 g, 2.93 mmol) and Na₂CO₃(0.647 g, 6.10 mmol) in DME-water (9:1, 10 mL) was degassed by purgingargon gas at rt. Pd(dppf)Cl₂.DCM (0.099 g, 0.121 mmol) was added to theabove mixture under nitrogen atmosphere at rt. The resulting mixture wasrefluxed for 4 h under nitrogen atmosphere. The reaction mixture wascooled to room temperature and filtered through a celite bed and washedwith ethyl acetate. The combined filtrate was concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (gradient elution with 10-25% EtOAc-hexanes) to affordtitle compound (609 mg 47.3%). LCMS (m/z): 479 (M+1)⁺.

e) Synthesis of6-(2-((6-(furan-2-yl)-N-isopropylnicotinamido)methyl)phenoxy) hexanoicacid

In 25-mL round bottom flask, ethyl6-(2-((6-(furan-2-yl)-N-isopropylnicotinamido)methyl)phenoxy)hexanoate(0.601 g, 1.25 mmol) was dissolved in THF (4 mL)-water (2 mL)-methanol(1 mL) at room temperature. Lithium hydroxide monohydrate (0.131 g, 3.14mmol) was added to the solution at and reaction mixture was stirred atrt for 3 h. The reaction mixture was concentrated under reduced pressureand residue obtained was dissolved in water and washed with diethylether. The aqueous phase was then acidified (HCl) and extracted withethyl acetate (30 mL×3). The combined extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography togive title compound (0.502 g, 89.2%). ¹H NMR (400 MHz, DMSO-d₆, 60° C.):δ 11.78 (s, 1H), 8.61 (s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.84 (s, 1H),7.74 (d, J=8.0 Hz, 1H), 7.27 (d, J=7.2 Hz, 1H), 7.20 (t, J=8.0 Hz, 1H),7.15 (d, J=3.6 Hz, 1H), 7.00-6.88 (m, 2H), 6.73-6.60 (m, 1H), 4.54 (s,2H), 4.18 (s, 1H), 3.98 (d, J=6.6 Hz, 2H), 2.23 (t, J=7.2 Hz, 2H), 1.76(br, 2H), 1.60-1.53 (m, 2H), 1.46 (br, 2H), 1.14 (d, J=6.4 Hz, 6H).LC-MS (m/z): 473.1 (M+Na)⁺. HPLC: 96.1%. (210 nm).

Example 2 Synthesis of6-(2-((5-(Furan-2-yl)-N-isopropylpicolinamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl6-(2-((5-bromo-N-isopropylpicolinamido)methyl)phenoxy)hexanoate

In 50-mL round bottom flask, EDCI.HCl (0.521 g, 2.7 mmol) and triethylamine (0.76 mL, 5.6 mmol) were sequentially added to a solution of ethyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate (0.7 g, 2.2 mmol),5-bromopicolinic acid (0.505 g, 2.5 mmol) and HOBt (0.418 g, 3.09 mmol)in dimethylformamide (7 mL) at rt under nitrogen atmosphere. Theresulting reaction mixture was stirred at for 16 h at room temperatureunder nitrogen atmosphere. The reaction mixture was concentrated underreduced pressure and residue obtained was purified by silica gel columnchromatography and eluting with 15% EtOAc-hexanes gave title compound(0.506 g, 46.9%). LCMS (m/z): 491 (M+1)⁺.

b) Synthesis of ethyl6-(2-((5-(furan-2-yl)-N-isopropylpicolinamido)methyl) phenoxy)hexanoate

In a 50-mL round bottom flask, a stirred suspension of ethyl6-(2-((5-bromo-N-isopropylpicolinamido)methyl)phenoxy)hexanoate (0.500g, 1.02 mmol), furan-2-yl boronic acid (0.125 g, 1.12 mmol) and Na₂CO₃(0.27 g, 2.55 mmol) in DME-water (9:1, 10 mL) was degassed by purgingargon gas at rt. Pd(dppf)Cl₂.DCM (0.041 mg, 0.05 mmol) was added to theabove solution under nitrogen atmosphere. The resulting reaction mixturewas refluxed for 4 h under nitrogen atmosphere. The reaction mixture wascooled to room temperature, filtered, and washed with ethyl acetate. Thecombined filtrate was concentrated under reduced pressure and residueobtained was purified by silica column chromatography (gradient elution,10% to 25% EtOAc-hexanes) to afford title compound (0.230 g 48.7%yield). LCMS (m/z): 501.3 (M+Na)⁺.

c) Synthesis of6-(2-((5-(furan-2-yl)-N-isopropylpicolinamido)methyl)phenoxy)hexanoicacid

In a 25-mL round bottom flask, ethyl6-(2-((5-(furan-2-yl)-N-isopropylpicolinamido)methyl)phenoxy)hexanoate(0.22 g, 0.4 mmol) was dissolved in THF (4 mL)-H₂O (2 mL)-MeOH (1 mL) atroom temperature. Lithium hydroxide monohydrate (0.048 g, 1.1 mmol) wasadded to the solution and resulting mixture was stirred at rt for 3 h.The reaction mixture was concentrated under reduced pressure and residueobtained was dissolved in water and washed with diethyl ether. Theaqueous phase was then acidified (HCl) and extracted with ethyl acetate(30 mL×3). The combined extract was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residueobtained was purified by silica gel column chromatography (elution with50% EtOAc-hexanes) to give title compound (0.068 g, 32.8%). ¹H NMR (400MHz, DMSO-d₆, 90° C.): δ 12.17-11.50 (br s, 1H), 8.91 (s, 1H), 8.12 (s,1H), 7.81 (s, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.30 (d, J=7.2 Hz, 1H), 7.18(t, J=7.2 Hz, 1H), 7.15-7.06 (m, 1H), 6.93-6.89 (m, 2H), 6.72-6.55 (m,1H), 4.63 (s, 2H), 4.25 (br, 1H), 4.02 (br s, 2H), 2.25 (t, J=7.2 Hz,2H), 1.78 (br, 2H), 1.63-0.60 (m, 2H), 1.57-1.42 (m, 2H), 1.13 (br s,6H). LCMS (m/z): 473.1 (M+Na)⁺. HPLC=97.49% (210 nm).

Example 3 Synthesis of6-(2-((3-(Furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

a) Synthesis of ethyl6-(2-((3-bromo-N-isopropylbenzamido)methyl)phenoxy)hexanoate

In a 50-mL round bottom flask, a stirred solution of ethyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate of example 1(0.500 g,1.62 mmol) in DMF (5 mL), was treated sequentially with 3-bromo benzoicacid (0.360 g, 1.79 mmol), EDCI.HCl (0.618 g, 3.24 mmol), HOBt (0.440 g,3.24 mmol), and triethylamine (0.68 mL, 4.8 mmol) at rt under nitrogenatmosphere. The reaction mixture was stirred at rt for 4 h undernitrogen atmosphere. Upon completion of the reaction (TLC), the reactionmixture quenched with cold water and extracted with ethyl acetate (50mL×3). The combined organic extract was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residueobtained was purified by silica gel column chromatography (gradientelution, 10-20% EtOAc-hexanes) to afford the title compound as clear oil(406 mg, 53.5%). LCMS (m/z): 491.9 (M+Na)⁺

b) Synthesis of methyl6-(2-((3-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy) hexanoate

In a resealable reaction tube, ethyl6-(2-((3-bromo-N-isopropylbenzamido)methyl) phenoxy)hexanoate (0.400 g,0.81 mmol), 2-furan boronic acid (0.113 g, 0.98 mmol) and Na₂CO₃ (1.32g, 12.45 mmol) were dissolved in DME (1.5 mL) and EtOH (1.5 mL) at rtunder nitrogen atmosphere. The solution was degassed by purging argongas at rt for 10 min. Pd(PPh₃)₃ (28.2 mg, 0.024 mmol) was added to theabove solution at rt under nitrogen. The resulting mixture was heated at90° C. for 4 h. Upon completion of the reaction (TLC), the reactionmixture was cooled to rt and diluted with cold water, before extractingwith ethyl acetate (50 mL×3). The combined organic extract was washedwith brine, dried over dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue obtained (0.4 g) was used in thenext step without further purification.

c) Synthesis of6-(2-((3-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid)

In a 25-mL round bottom flask, methyl6-(2-((3-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate(0.40 g, 0.83 mmol) was dissolved in THF (10 mL)-water (3 mL)-ethanol (3mL) mixture at rt. Lithium hydroxide monohydrate (0.105 g, 2.51 mmol)was added to the above solution and the reaction mixture was stirred at50° C. for 4 h. Upon completion of the reaction (TLC), the reactionmixture was concentrated under reduced pressure. The residue obtainedwas diluted with cold water and acidified with HCl (2N), beforeextracting with ethyl acetate (50 mL×3). The combined organic extractwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure to afford title compound (180 mg, 47.8%) asoff-white solid. 1′H NMR (400 MHz, DMSO-d₆, 60° C.): δ 11.82 (s, 1H),7.75-7.69 (m, 3H), 7.48 (br, 1H), 7.31-7.27 (m, 3H) 7.21 (t, J=7.6 Hz,1H), 6.96 (t, J=7.2 Hz, 2H), 6.66-6.54 (br, 1H), 4.53 (s, 2H), 4.25-3.89(m, 1H), 2.26-2.21 (m, 2H), 1.75 (br, 2H), 1.65-1.36 (m, 4H), 1.20-1.02(br s, 6H). LCMS (m/z): 450.4 (M+1)⁺. HPLC: 6.65% (210 nm).

Example 4 Synthesis of6-(2-((N-isopropyl-4-methylbenzamido)methyl)phenoxy)hexanoic acid

a) Synthesis of ethyl6-(2-((N-isopropyl-4-methylbenzamido)methyl)phenoxy)hexanoate

In a 25-mL round bottom flask, a stirred solution of ethyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate (0.51 g, 1.66 mmol) ofexample I(b) in DMF (5 mL), was treated sequentially with4-methylbenzoic acid (0.221 g, 1.54 mmol), HBTU (1.84 g, 4.86 mmol) andtriethylamine (0.818 g, 8.10 mmol) at rt under nitrogen atmosphere. Thereaction mixture was stirred at rt for 18 h. Upon completion of thereaction (TLC), the reaction mixture was diluted with cold water andextracted with ethyl acetate (25 mL×2). The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue obtained was purified by silica gel columnchromatography (elution 15% EtOAc-hexanes) to give title compound (0.450g, 65%) as a clear oil. LCMS (m/z): 426.3 (M+1)⁺.

b) Synthesis of6-(2-((N-isopropyl-4-methylbenzamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, ethyl6-(2-((N-isopropyl-4-ethylbenzamido)methyl)phenoxy)hexanoate (0.400 g,0.94 mmol) was dissolved in THF (2 mL)-water (1 mL) mixture at rt.Lithium hydroxide monohydrate (0.197 g, 4.7 mmol) was added to the abovesolution and the reaction mixture was stirred at rt for 18 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure and the residue obtained was diluted with water.The aqueous solution was acidified with 2N HCl and extracted with ethylacetate (10 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude product was washed with diethyl ether and n-pentane, solventdecanted and residue dried under reduced pressure to afford the titleproduct (0.258 g, 69%) as clear oil. ¹H NMR (400 MHz, DMSO-d₆, 60° C.) δ11.81 (s, 1H), 7.40-7.12 (m, 6H), 7.07-6.82 (m, 2H), 4.51 (s, 2H), 4.13(br, 1H), 4.01 (br t, J=6.0 Hz, 2H), 2.34 (s, 3H), 2.24 (t, J=7.2 Hz,2H), 1.78-1.74 (m, 2H), 1.63-1.57 (m, 2H), 1.49-1.47 (m, 2H), 1.08 (d,J=6.4 Hz, 6H). LCMS (m/z): 398.1 (M+1)⁺. HPLC: 96.8% (210 nm).

Example 5 Synthesis of6-(2-((4-fluoro-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

a) Synthesis of ethyl6-(2-((4-fluoro-N-isopropylbenzamido)methyl)phenoxy)hexanoate

In a 25-mL round bottom flask, a stirred solution of ethyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate of example I(b) (0.500 g,1.62 mmol) in DMF (7 mL), was treated sequentially with 4-fluorobenzoicacid (0.272 g, 1.94 mmol), EDCI.HCl (0.370 g, 1.94 mmol), HOBt (0.261 g,1.94 mmol) and diisopropylethylamine (0.313 g, 2.43 mmol) at rt undernitrogen atmosphere. The reaction mixture was stirred at rt for 18 hunder nitrogen atmosphere.

Upon completion of the reaction (TLC), the reaction mixture was dilutedwith cold water and extracted with ethyl acetate (25 mL×2). The combinedorganic extract was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography (elution, 15% EtOAc-hexanes) to givethe title compound (0.41 g, 58.8%) as clear oil. LCMS (m/z): 430.0(M+1)⁺.

b) Synthesis of6-(2-((4-fluoro-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, ethyl6-(2-((4-fluoro-N-isopropylbenzamido)methyl) phenoxy)hexanoate (0.400 g,0.93 mmol) was dissolved in THF (2 mL)-water (1 mL) mixture at rt.Lithium hydroxide monohydrate (0.195 g, 4.6 mmol) was added to the abovesolution and the reaction mixture was stirred at rt for 18 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure and the residue obtained was diluted with water.The aqueous solution was acidified with 2N HCl and extracted with ethylacetate (10 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography(elution 30% EtOAc-hexanes) to give the title compound (0.110 g, 29.4%)as clear oil. ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 12.08 (br s, 1H),7.49 (br, 2H), 7.26-7.18 (m, 4H), 6.96-6.91 (m, 2H), 4.50 (s, 2H), 4.10(s, 1H), 4.00 (d, J=6.4 Hz, 2H), 2.24 (t, J=7.2 Hz, 2H), 1.86-1.68 (m,2H), 1.62-1.58 (m, 2H), 1.51-1.48 (m, 2H) 1.09 (d, J=6.4 Hz, 6H). LCMS(m/z): 402.1 (M+1)⁺. HPLC: 95.32% (210 nm).

Example 6 Synthesis of6-(2-((N-isopropyl-4-(trifluoromethoxy)benzamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl6-(2-((N-isopropyl-4-(trifluoromethoxy)benzamido)methyl)phenoxy)hexanoate

In a 50-mL round bottom flask, a stirred solution of methyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate of example I(b) (0.50 g,1.63 mmol) in DCM (9 mL)-DMF (1 mL), was treated with4-trifluoromethoxybenzoic acid (0.32 g, 1.55 mmol), HBTU (1.7 g, 4.65mmol) and triethylamine (0.7 mL, 5.0 mmol) at rt under nitrogenatmosphere. The reaction mixture was stirred at rt for 3 h undernitrogen atmosphere. Upon completion of the reaction (TLC), the reactionmixture quenched with water and extracted with ethyl acetate (50 mL×3).The combined organic extract was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue obtained waspurified by silica gel column chromatography (gradient elution, 10-20%EtOAc-hexanes) to afford the title compound (0.312 g, 38.6%) as a clearoil. LCMS (m/z): 496 (M+1)⁺.

b) Synthesis of6-(2-((N-isopropyl-4-(trifluoromethoxy)benzamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, ethyl6-(2-((N-isopropyl-4-(trifluoromethoxy)benzamido)methyl)phenoxy)hexanoate(0.250 g, 0.50 mmol) was dissolved in THF (10 mL), water (5 mL) and EtOH(5 mL) mixture at rt. Lithium hydroxide monohydrate (0.636 mg, 1.51mmol) was added to the above solution and the reaction mixture wasstirred at rt for 18 h. Upon completion of the reaction (TLC), thereaction mixture was concentrated under reduced pressure and the residueobtained was diluted with water. The aqueous solution was acidified with1N HCl and extracted with ethyl acetate (50 mL×3). The combined organicextract was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography (elution 30% EtOAc-hexanes) to givethe title compound (0.230 g, 97.5%) as clear oil. ¹H NMR (400 MHz,DMSO-d₆, 60° C.): δ 11.9 (br, 1H), 7.56 (m, 2H), 7.44-7.35 (m, 2H),7.28-7.15 (m, 2H), 7.00-6.88 (m, 2H), 4.52 (s, 2H), 4.21-4.04 (m, 1H),4.00 (t, J=6.4 Hz, 2H), 2.24 (t, J=7.2 Hz, 2H), 1.78-1.75 (m, 2H),1.63-1.58 (m, 2H), 1.53-1.42 (m, 2H), 1.11 (d, J=6.4 Hz, 6H). LCMS(m/z): 466.6 (M−1)⁺. HPLC: 97.89% (210 nm).

Example 7 Synthesis of6-(2-((4-(dimethylamino)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid

The title compound (0.306 g) was prepared from methyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate (0.500 g, 1.6 mmol) ofExample I(b) and 4-N,N-dimethyl amino benzoic acid (0.26 g, 1.57 mmol)following the procedure of Example-6. ¹H NMR (400 MHz, DMSO-d₆, 60° C.):δ 7.32-7.25 (m, 2H), 7.24-7.14 (m, 2H), 7.00-6.87 (m, 2H), 6.71 (d,J=8.8 Hz, 2H), 4.51 (s, 2H), 4.25-4.21 (m, 1H), 4.02 (t, J=6.3 Hz, 2H),2.94 (s, 6H), 2.23 (t, J=7.2 Hz, 2H), 1.78-1.73 (m, 2H), 1.62-1.56 (m,2H), 1.53-1.42 (m, 2H), 1.09 (d, J=6.4 Hz, 6H). LCMS (m/z): 427.25(M+1)⁺. HPLC: 96.81% (210 nm).

Example 8 Synthesis of6-(2-((4-Cyano-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

The title compound (0.070 g) was prepared from methyl6-(2-((isopropylamino)methyl)phenoxy) hexanoate (0.50 g, 1.62 mmol) ofExample I(b) and 4-cyanobenzoic acid (0.263 g, 1.79 mmol) following theprocedure of Example-6 to afford the product. 11H NMR (400 MHz, DMSO-d₆,90° C.) δ 12.0 (br s, 1H), 7.97 (d, J=7.6 Hz, 2H), 7.77 (br, 0.8H), 7.69(d, J=7.6 Hz, 2H), 7.49 (br, 0.9H), 7.24-1.18 (m, 3H), 6.99-6.91 (m,3H), 4.55 (s, 2H), 4.42-4.32 (br, 1H), 4.03 (br, 2H), 3.84 (br, 2H),2.24 (br, 2.8H), 1.79 (br, 2H), 1.65-1.41 (br, 6H), 1.33-1.17 (br,3.5H), 1.04 (d, J=6 Hz, 6H). (NMR peaks were broad due to presence ofrotamers). LCMS (m/z): 431.2 (M+Na)⁺. HPLC=99.17% (210 nm).

Example 9 Synthesis of6-(2-((N-isopropyl-4-methoxybenzamido)methyl)phenoxy)hexanoic acid

The title compound (0.235 g) was prepared from methyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate (0.500 g, 1.62 mmol) ofExample I(b) and 4-methoxybenzoic acid (0.271 g, 1.8 mmol) following theprocedure of Example-6. ¹H NMR (400 MHz, DMSO-d₆, 60° C.) δ 11.81 (s,1H), 7.42-7.34 (m, 2H), 7.26-7.15 (m, 2H), 6.99-6.91 (m, 4H), 4.51 (s,2H), 4.17-4.14 (m, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.80 (s, 3H), 2.24 (t,J=7.2 Hz, 2H), 1.78-1.74 (m, 2H), 1.64-1.56 (m, 2H), 1.51-1.45 (m, 2H),1.09 (d, J=6.4 Hz, 6H). LCMS (m/z): 431.2 (M+Na)⁺. HPLC: 97.61% (210nm).

Example 10 Synthesis of6-(2-((4-chloro-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

The title compound (0.275 g) was prepared from methyl6-(2-((isopropylamino)methyl) phenoxy)hexanoate (0.500 g, 1.62 mmol) ofexample I(b) and 4-chlorobenzoic acid (0.28 g, 1.8 mmol) following theprocedure of Example-6. ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 7.47-7.45(m, 4H), 7.24-7.18 (m, 2H), 6.96-6.91 (m, 2H), 4.50 (s, 2H), 4.18-3.95(m, 3H), 2.24 (t, J=7.2 Hz, 2H), 1.77-1.72 (m, 2H), 1.64-1.47 (m, 4H),1.09 (d, J=6.4 Hz, 6H). LCMS (m/z): 440.2 (M+Na)⁺. HPLC: 97.5% (210 nm).

Example 11 Synthesis of6-(2-((4-acetyl-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

The title compound (0.150 g) was prepared from methyl6-(2-((isopropylamino)methyl) phenoxy)hexanoate (0.50 g, 1.62 mmol) ofExample I(b) and 4-acetyl benzoic acid (0.32 g, 1.95 mmol) using theprocedure of Example-6. ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 11.84 (s,1H), 8.07-7.95 (br, 2H), 7.56 (br, 2H), 7.30-7.18 (m, 2H), 6.95 (t,J=7.2 Hz, 2H), 4.53 (br s, 2H), 4.01 (br, 3H), 2.60 (s, 3H), 2.24 (t,J=7.2 Hz, 2H), 1.78-1.75 (m, 2H), 1.62-0.158 (m, 2H), 1.51-1.46 (m, 2H),1.01 (br s, 6H). LCMS (m/z): 426.2 (M+1)⁺. HPLC=95.21% (210 nm).

Example 12 Synthesis of6-(2-((N-isopropyl-4-(methylsulfonyl)benzamido)methyl)phenoxy)hexanoicacid

The title compound (0.130 g) was prepared from methyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate (0.5 g, 1.62 mmol) ofexample I(b) and 4-methane sulfonyl benzoic acid (0.39 g, 1.95 mmol)following the procedure of Example-6. ¹H NMR (400 MHz, DMSO-d₆, 60° C.):δ 12.03 (br s, 1H), 7.94 (br, 2H), 7.63 (br, 2H), 7.23 (d, J=7.2 Hz,1H), 7.17 (t, J=7.6 Hz, 1H), 6.91 (t, J=7.2 Hz, 2H), 4.54 (br, 2H), 4.01(br, 3H), 3.18 (s, 3H), 2.21 (t, J=7.3 Hz, 2H), 1.72 (br, 2H), 1.62-1.59(m, 2H), 1.48 (br, 2H), 1.08 (br s, 6H). LCMS (m/z): 462.2 (M+1)⁺. HPLC:98.89 (210 nm).

Example 13 Synthesis of6-(2-((N-isopropyl-4-(pyrrolidin-1-yl)benzamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl6-(2-((4-bromo-N-isopropylbenzamido)methyl)phenoxy)hexanoate

In a 25-mL round bottom flask, a stirred solution of ethyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate (0.76 g, 2.48 mmol) ofexample I(b) in DMF (2 mL), was treated sequentially with 4-bromobenzoic acid (0.500 g, 2.48 mmol), HBTU (2.81 g, 7.44 mmol) andtriethylamine (0.78 g, 7.44 mmol) at rt under nitrogen atmosphere. Thereaction mixture was stirred at rt for 3 h. Upon completion of thereaction (TLC), the reaction mixture was diluted with cold water andextracted with ethyl acetate (25 mL×2). The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue obtained was purified by silica gel columnchromatography (elution 15% EtOAc-hexanes) to give title compound (0.660g, 54.3%) as a clear oil. LCMS (m/z): 490.1 (M+1)⁺.

b) Synthesis of ethyl6-(2-((N-isopropyl-4-(pyrrolidin-1-yl)benzamido)methyl)phenoxy)hexanoate

In a resealable reaction tube, the solution of ethyl6-(2-((4-bromo-N-isopropylbenzamido)methyl)phenoxy)hexanoate (0.40 g,0.81 mmol) in toluene (40 mL), was treated sequentially with pyrrolidinehydrochloride (0.115 g, 1.06 mmol), rac-BINAP (0.101 g, 0.16 mmol) andCs₂CO₃ (1.32 g, 4.05 mmol) at rt under nitrogen atmosphere. The mixturewas degassed by purging with argon gas and thereafter treated withPd₂(dba)₃ (0.134 mg, 0.14 mmol) under atmosphere. The resulting reactionmixture was heated at 70° C. for 12 h. Upon completion of the reaction(TLC), the reaction mixture was cooled to rt and diluted with cold waterbefore extracting with ethyl acetate (100 mL×3).The combined organicextract was washed with brine and concentrated under reduced pressure.The residue obtained was purified by silica gel column chromatography(gradient elution, 10-20% EtOAc-hexanes) to afford title compound (308mg, 79.2%). LCMS (m/z): 481.1 (M+1)⁺.

c) Synthesis of6-(2-((N-isopropyl-4-(pyrrolidin-1-yl)benzamido)methyl)phenoxy) hexanoicacid

In a 25-mL round bottom flask, ethyl6-(2-((N-isopropyl-4-(pyrrolidin-1-yl)benzamido)methyl)phenoxy)hexanoate(0.30 g, 0.62 mmol) was dissolved in THF (10 mL)-water (3 mL)-EtOH (3mL) mixture at rt. Lithium hydroxide monohydrate (78.7 mg, 1.87 mmol)was added to the above solution and the reaction mixture was stirred atrt for 12 h. Upon completion of the reaction (TLC), the reaction mixturewas concentrated under reduced pressure and the residue obtained wasdiluted with water. The aqueous solution was acidified with 1N HCl andextracted with ethyl acetate (50 mL×3). The combined organic extract waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue obtained was purified by silica gel columnchromatography (elution 5% MeOH—CHCl₃) to give the title compound (120mg, 42.5%) as off-white solid. 1H NMR (400 MHz, DMSO-d₆, 90° C.): δ 7.28(d, J=8.0 Hz, 2H), 7.25-7.15 (m, 2H), 7.01-6.87 (m, 2H), 6.54 (d, J=8.0Hz, 2H), 4.51 (s, 2H), 4.26-4.18 (m, 1H), 4.02 (t, J=6.0 Hz, 2H),3.32-3.22 (m, 4H), 2.24 (t, J=7.2 Hz, 2H), 2.03-1.92 (m, 4H), 1.78-1.74(m, 2H), 1.62-1.58 (m, 2H), 1.53-1.42 (m, 2H), 1.09 (d, J=6.4 Hz, 6H).LCMS (m/z): 453.4 (M+1)⁺. HPLC: 97.99% (210 nm).

Example 14 Synthesis of6-(2-((4-(Cyclopropylethynyl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid a) Synthesis of ethyl6-(2-((4-(cyclopropylethynyl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate

In a resealable tube, ethyl6-(2-((4-bromo-N-isopropylbenzamido)methyl)phenoxy) hexanoate fromexample-13(a) (0.40 g, 0.86 mmol), cyclopropyl acetylene (0.534 g, 8.03mmol) CuI (0.015 g, 0.08 mmol), were dissolved in dry DMF (1 mL) at rtunder nitrogen atmosphere. The solution was degassed and treated withPdCl₂(PPh₃)₂ (28.5 mg, 0.04 mmol) and triethyl amine (0.24 mL, 2.4 mmol)under argon atmosphere. The resulting mixture was heated at 60° C. for24 h. Upon completion of the reaction (TLC), the reaction mixture wascooled to room temperature, diluted with cold water and extracted withEtOAc (3×50 mL). The combined organic extract was washed with brine andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography and gradient elution with 10-20%EtOAc-hexanes gave the title compound (316 mg, 77.5%). LCMS (m/z): 476.3(M+1)⁺.

b) Synthesis of6-(2-((4-(cyclopropylethynyl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

In a 25-ml round bottom flask, ethyl6-(2-((4-(cyclopropylethynyl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate(0.250 g, 0.52 mmol) was dissolved in THF (10 mL), water (3 mL) andethanol (3 mL) mixture at rt. Lithium hydroxide monohydrate (0.066 mg,1.57 mmol) was added to the above solution and the reaction mixture wasstirred at rt for 12 h. Upon completion of the reaction (TLC), thereaction mixture was concentrated under reduced pressure and the residueobtained was diluted with water and acidified with 1N HCl and extractedwith ethyl acetate (50 mL×3). The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by preparative HPLC to givethe title compound (170 mg, 72.21%). ¹H NMR (400 MHz, DMSO-d₆, 60° C.):δ 11.88 (br s, 1H), 7.38-7.34 (m, 4H), 7.27-7.15 (m, 2H), 6.99-6.87 (m,2H), 4.50 (s, 2H), 4.15-4.03 (m, 1H), 4.00 (t, J=6.4 Hz, 2H), 2.24 (t,J=7.2 Hz, 2H), 1.76-1.74 (m, 2H), 1.66-1.41 (m, 4H), 1.08 (d, J=6.4 Hz,6H), 0.93-0.86 (m, 2H), 0.81-0.69 (m, 2H). LCMS (m/z): 448.1 (M+1)⁺.HPLC: 99.49% (210 nm).

Example 15 Synthesis of6-(2-((4-Cyclopropoxy-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

a) Synthesis of methyl 4-cyclopropoxybenzoate

In a resealable reaction tube, methyl 4-hydroxybenzoate (2.0 g, 13.14mmol) and bromocyclopropane (5.26 g, 43.47 mmol) were dissolved in dryDMF (10 mL) at rt under nitrogen atmosphere. K₂CO₃ (6.0 g, 43.47 mmol)was added to the above solution and resulting reaction mixture washeated in microwave at 140° C. for 2 h. Upon completion of reaction(TLC), the reaction mixture was cooled to rt and diluted with water,before extracting diethyl ether (3×100 mL). The combined organic extractwas washed with brine and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography(eluting with 0-10% EtOAc/hexanes) to afford title compound (520 mg).LCMS (m/z): 192.9 (M+1)⁺.

b) Synthesis of 4-cyclopropoxybenzoic acid

The stirred solution of methyl 4-cyclopropoxybenzoate (0.40 g, 2.08mmol) in THF (10 mL)-MeOH (2 mL) was treated with 1N NaOH (10 mL) at rt.The reaction mixture was stirred at rt until completion of the reaction(TLC). The reaction mixture was concentrated under reduced pressure;residue obtained was acidified with 1N HCl and extracted with EtOAc (50mL×3). The combined organic extract washed with brine and concentratedunder reduced pressure to afford title compound which was used in nextstep without any further purifications (178 mg, crude).

c) Synthesis of ethyl6-(2-((4-cyclopropoxy-N-isopropylbenzamido)methyl)phenoxy) hexanoateisopropylbenzamido)methyl)phenoxy)hexanoate

In a 50-mL round bottom flask, a stirred solution of ethyl6-(2-((isopropylamino)methyl) phenoxy)hexanoate (0.27 g, 0.87 mmol) fromexample 1(b) in DMF (5 mL) was treated sequentially with4-cyclopropoxybenzoic acid (0.150 g, 0.87 mmol), EDCI.HCl (0.336 g, 1.75mmol), HOBt (0.239 g, 1.82 mmol), and triethylamine (0.88 mL, 2.64 mmol)at rt under nitrogen atmosphere. The reaction mixture was stirred at rtfor 12 h. Upon completion of the reaction (TLC), the reaction mixturewas diluted with cold water and extracted with ethyl acetate (50 mL×3).The combined organic extract was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue obtained waspurified by silica gel column chromatography (elution 20% EtOAc-hexanes)to afford the title compound (130 mg, 31.7%) as clear oil. LCMS (m/z):468.2 (M+1)⁺.

d) Synthesis of6-(2-((4-cyclopropoxy-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, methyl6-(2-((4-cyclopropoxy-N-isopropylbenzamido)methyl)phenoxy)hexanoate(0.10 g, 0.21 mmol) was dissolved in THE (3 mL)-water (1 mL)-EtOH (1 mL)mixture at rt. Lithium hydroxide monohydrate (0.027 g, 0.63 mmol) wasadded to the above solution and the reaction mixture was stirred at rtfor 12 h. Upon completion of the reaction (TLC), the reaction mixturewas concentrated under reduced pressure and the residue obtained wasdiluted with water. The aqueous solution was acidified with 2N HCl andextracted with ethyl acetate (10 mL×2). The combined organic extract waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue obtained was purified by preparative HPLCto give the title compound (56 mg, 60.6%) as off white solid. ¹H NMR(400 MHz, DMSO-d₆, 60° C.) δ 7.42-7.32 (m, 2H), 7.26-7.14 (m, 2H),7.12-7.03 (m, 2H), 7.03-6.85 (m, 2H), 4.51 (s, 2H), 4.21-4.13 (m, 1H),4.01 (t, J=6.0 Hz, 2H), 3.88-3.86 (m, 1H), 2.24 (t, J=7.2 Hz, 2H),1.79-1.74 (m, 2H), 1.62-1.58 (m, 2H), 1.49-1.45 (m, 2H), 1.09 (d, J=6.4Hz, 6H), 0.87-0.75 (m, 2H), 0.71-0.62 (m, 2H). LCMS (m/z): 440.2 (M+1)⁺.HPLC=98.85% (210 nm).

Example 16 Synthesis ofN-(2-(4-(2H-Tetrazol-5-yl)butoxy)benzyl)-4-(furan-2-yl)-N-isopropylbenzamide

a) Synthesis of 2-((isopropylamino)methyl)phenol

Isopropyl amine (2.65 g, 44.8 mmol) and salicylaldehyde (5.0 g, 40.9mmol) were dissolved in 1,2-dichloroethane (50 mL) at rt. AcOH (16 mL)was added slowly to the above solution (exothermic). Sodiumtriacetoxyborohydride (19.0 g, 89.6 mmol) was added in portions to themixture and resulting reaction mixture was stirred at rt for 4 h undernitrogen atmosphere. The reaction mixture was quenched by addingsaturated sodium carbonate solution, and extracted with ethyl acetate.The ethyl acetate extract was washed with brine and dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford the titlecompound (6.70 g, 88.7%). LCMS (m/z): 349.9 (M+1)⁺.

b) Synthesis of 4-bromo-N-(2-hydroxybenzyl)-N-isopropylbenzamide

In 100-mL round bottom flask, EDCI.HCl (9.0 g, 47 mmol) and DIPEA (17mL, 97.6 mmol) were added sequentially to a solution of2-((isopropylamino)methyl)phenol (6.50 g, 39.3 mmol), 4-bromobenzoicacid (9.50 g, 47.3 mmol) and HOBt (7.20 g, 53.3 mmol) indimethylformamide (65 mL) at rt under nitrogen atmosphere. The resultingreaction mixture was stirred at rt for 16 h under nitrogen atmosphere.The mixture was concentrated under reduced pressure and residue obtainedwas purified by silica gel column chromatography (elution 10%EtOAc-hexanes) to give title compound (6.08 g, 46.1%). LCMS (m/z): 336.1(M+1)⁺.

c) Synthesis of 4-(furan-2-yl)-N-(2-hydroxybenzyl)-N-isopropylbenzamide

In a 50-mL round bottom flask, a stirred suspension of4-bromo-N-(2-hydroxybenzyl)-N-isopropylbenzamide (0.70 g, 2 mmol),furan-2-boronic acid (0.269 g, 2.4 mmol) and Na₂CO₃ (0.533 g, 5 mmol) inDME (9 mL)-water (1 mL) was degassed with argon gas. Pd(dppf)C₂lDCM(0.082 g, 0.1 mmol) was added to the above mixture at rt under nitrogenatmosphere. The resulting reaction mixture was refluxed for 4 h undernitrogen atmosphere. The reaction mixture was cooled to rt, filtered andresidue washed with ethyl acetate. The combined filtrate wasconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography (gradient elution 10-20%EtOAc-hexanes) to afford title compound (512 mg, 76.4%). LCMS (m/z):336.1 (M+1)⁺.

d) Synthesis ofN-(2-(4-cyanobutoxy)benzyl)-4-(furan-2-yl)-N-isopropylbenzamide

In 25-mL round bottom flask, a solution of4-(furan-2-yl)-N-(2-hydroxybenzyl)-N-isopropylbenzamide (0.50 g, 1.49mmol) in DMF (7.5 mL) was treated with potassium carbonate (0.308 g, 2.2mmol) and 5-bromopentane nitrile (0.289 g, 1.7 mmol) at rt undernitrogen atmosphere. The reaction mixture was heated at 80° C. for 3 h.Upon completion of the reaction (TLC), the reaction mixture was cooledto rt, filtered and washed with EtOAc. The combined filtrate wasconcentrated under reduced pressure. The residue obtained was dilutedwater (50 mL) and extracted with EtOAc (200 mL).The organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue obtained was purified by silica gel columnchromatography (elution 10% EtOAc-hexanes) to give title compound (0.599g, 96.7%). LCMS (m/z): 417.1 (M+1)⁺.

e) Synthesis ofN-(2-(4-(2H-tetrazol-5-yl)butoxy)benzyl)-4-(furan-2-yl)-N-isopropylbenzamide

In a 25-mL resealable reaction tube, a solution ofN-(2-(4-cyanobutoxy)benzyl)-4-(furan-2-yl)-N-isopropylbenzamide (0.50 g,1.2 mmol) in DMF (7.5 mL) was treated with NaN₃ (0.39 g, 6.0 mmol) andtriethylamine hydrochloride (0.494 g, 3.58 mmol) at rt under nitrogenatmosphere. The reaction mixture was stirred 135° C. for 24 h. Uponcompletion of the reaction (TLC), the reaction mixture was cooled to rtand neutralized with saturated Na₂CO₃, before extracting with EtOAc (25mL×3). The combined organic extract was washed with water, brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was purified by preparative HPLC to give the titlecompound (120 mg, 21.8%). ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 7.76-7.72(m, 3H), 7.47 (d, J=7.6 Hz, 2H), 7.31-7.15 (m, 2H), 7.00-6.92 (m, 3H),6.61 (br, 1H), 4.52 (s, 2H), 4.09 (d, J=37.6 Hz, 3H), 2.95 (t, J=7.2 Hz,2H), 2.00-1.71 (m, 4H), 1.09 (d, J=6.4 Hz, 6H). LCMS (m/z): 482.1(M+Na)⁺. HPLC: 99.3% (210 nm).

Example 175-(2-((4-(Furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)pentanoic acid

a) Synthesis of ethyl5-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)pentanoate

In a 25-mL round bottom flask, a stirred solution of4-(furan-2-yl)-N-(2-hydroxybenzyl)-N-isopropylbenzamide (0.30 g, 0.895mmol) of example 16(c) in DMF (5 mL) was treated with potassiumcarbonate (0.148 g, 1.09 mmol) and ethyl 5-bromopentanoate (0.205 g,0.985 mmol) at rt under nitrogen atmosphere. The reaction mixture washeated at 90° C. for 18 h under nitrogen atmosphere. Upon completion ofthe reaction (TLC), the reaction mixture was cooled at rt, diluted withcold water and extracted with ethyl acetate (10 mL×2). The combinedorganic extract was washed with water, brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue obtained waspurified by silica gel column chromatography (elution 30% EtOAc-hexanes)to give title compound (0.31 g, 74.8%) as clear oil. LCMS (m/z): 464.3(M+1)*.

b) Synthesis of5-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)pentanoic acid

In a 25-mL round bottom flask, ethyl5-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)pentanoate(0.30 g, 0.64 mmol) was dissolved in THF (3 mL)-water (3 mL) at rt.Lithium hydroxide monohydrate (0.135 g, 3.23 mmol) was added to theabove solution and the reaction mixture was stirred at rt for 18 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure and the residue obtained was diluted with water.The aqueous solution was acidified with 2N HCl and extracted with ethylacetate (10 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was purified by preparative HPLC to give the titlecompound (0.111 g, 39.4%) as sticky liquid. ¹H NMR (400 MHz, DMSO-d₆,60° C.): δ 11.87 (s, 1H), 7.83-7.74 (m, 3H), 7.51 (d, J=7.6 Hz, 2H),7.33-7.20 (m, 2H), 7.06-6.93 (m, 3H), 6.65 (dd, J=3.2, 1.6 Hz, 1H), 4.58(s, 2H), 4.19 (br, 1H), 4.06 (t, J=6.0 Hz, 2H), 2.35 (t, J=6.8 Hz, 2H),1.92-1.65 (m, 4H), 1.15 (d, J=6.4 Hz, 6H). LCMS (m/z): 436.5 (M+1)⁺.HPLC: 98.85% (210 nm).

Example 187-(2-((4-(Furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)heptanoic acid

a) Synthesis of ethyl7-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy) heptanoate

In a 25-mL round bottom flask, a stirred solution of4-(furan-2-yl)-N-(2-hydroxybenzyl)-N-isopropylbenzamide (0.450 g, 1.34mmol) of example 16(c) in DMF (5 mL) at rt under reduced pressure.Potassium carbonate (0.222 g, 1.60 mmol) and ethyl 7-bromoheptanoate(0.35 g, 1.67 mmol) were added at the above solution at rt undernitrogen atmosphere. The reaction mixture was heated at 90° C. for 4 h.Upon completion of the reaction (TLC), the reaction mixture was cooledto rt, diluted with cold water and extracted with ethyl acetate (30mL×2). The combined organic extract was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residueobtained was purified by silica gel column chromatography (elution 10%EtOAc-hexanes) to give title compound (0.39 g, 63%) as clear oil. LCMS(m/z): 492.1 (M+1)⁺.

b) Synthesis of7-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)heptanoic acid

In a 25-mL round bottom flask, methyl7-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)heptanoate(0.39 g, 0.79 mmol) was dissolved in THF (3 mL)-water (3 ml) at rt.Lithium hydroxide monohydrate (0.266 g, 6.35 mmol) was added to theabove solution and the reaction mixture was stirred at rt for 18 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure and the residue obtained was diluted with water.The aqueous solution was washed with diethyl ether (25 mL) and acidifiedwith 1N HCl. The solid precipitated was filtered, washed with n-pentaneand dried under reduced pressure to give the title compound (0.209 g,57.1%). ¹H NMR (400 MHz, DMSO-d₆, 60° C.) δ 7.81-7.67 (m, 3H), 7.46 (d,J=7.6 Hz, 2H), 7.26 (d, J=7.2 Hz, 1H), 7.20 (t, J=7.2 Hz, 1H), 7.05-6.86(m, 3H), 6.61 (dd, J=3.2, 1.6 Hz, 1H), 4.53 (s, 2H), 4.16 (br, 1H), 4.01(t, J=6.3 Hz, 2H), 2.21 (t, J=7.2 Hz, 2H), 1.80-1.72 (m, 2H), 1.56-1.51(m, 2H), 1.49-1.30 (m, 4H), 1.11 (d, J=6.4 Hz, 6H). LCMS (m/z): 486.2(M+Na)⁺. HPLC: 96.32% (210 nm).

Example 193-(2-(2-((4-(Furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethoxy)propanoicacid

a) Synthesis of ethyl 3-(2-(benzyloxy)ethoxy)propanoate

In a 250-mL round bottom flask, a stirred solution of2-(benzyloxy)ethanol (9.0 g, 59.1 mmol) in of anhydrous THF (100 mL),was treated with ethyl propenoate (5.62 g, 49.2 mmol) and sodium metal(0.0013 g, 0.591 mmol) at rt under nitrogen atmosphere. The reactionmixture was stirred at rt for 18 h. Upon completion of the reaction(TLC), the reaction mixture quenched with cold water and extracted withethyl acetate (250 mL×2). The combined organic extract was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography and eluting with 10% EtOAc-hexanes gave title compound(2.51 g, 16.8%) as a clear oil. LCMS (m/z): 253.1 (M+1)⁺.

b) Synthesis of ethyl 3-(2-hydroxyethoxy)propanoate

In a 100-mL round bottom flask, a stirred solution of ethyl3-(2-(benzyloxy) ethoxy)propanoate (2.0 g,7.93 mmol) in 20 mL of EtOAc,was treated with palladium on carbon (10 wt %, activated carbon support,0.50 g) under nitrogen atmosphere. The stirred reaction mixture washydrogenated (balloon pressure) at rt for 4 h. Upon completion of thereaction (TLC), the reaction mixture was filtered over celite bed andwashed with ethyl acetate (25 mL×2). The combined filtrate wasconcentrated under reduced pressure to give title compound as clear oil.The crude product was taken to next step without any purification.(1.203 g). LCMS (ESI, m/z): 163.0 (M+1)⁺.

c) Synthesis of ethyl 3-(2-bromoethoxy)propanoate

In a 25-mL round bottom flask, a stirred solution of ethyl3-(2-hydroxyethoxy)propanoate (0.20 g, 1.23 mmol) in of dry THF (5 mL)was treated sequentially with triphenylphosphine (0.386 g, 1.47 mmol)and carbon tetrabromide (0.614 g, 1.85 mmol) at rt under nitrogenatmosphere. The reaction mixture was stirred at rt for 3 h. Uponcompletion of the reaction (TLC), the reaction mixture quenched withcold water and extracted with ethyl acetate (10 mL×2). The combinedorganic extract was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography (elution 10% EtOAc-hexanes) toafford the title product as clear oil. (0.150 g, 54.1%). LCMS (m/z):226.9 (M+2)⁺.

d) Synthesis of ethyl3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethoxy)propanoate

In a 25-mL round bottom flask, a stirred solution of4-(furan-2-yl)-N-(2-hydroxybenzyl)-N-isopropylbenzamide (0.50 g, 1.49mmol) of Example 16c in DMF (5 mL) was treated with potassium carbonate(0.247 g, 1.78 mmol) and ethyl 3-(2-bromoethoxy)propanoate (0.369 g,1.63 mmol) at rt under nitrogen atmosphere. The reaction mixture washeated at 90° C. for 18 h. Upon completion of the reaction (TLC), thereaction mass cooled to rt, diluted with cold water and extracted withethyl acetate (10 mL×2). The combined organic extract was washed withwater, brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (elution 30% EtOAc-hexanes) to afford the title compound(0.421 g, 59%) as a clear oil. LCMS (m/z): 480 (M+1)⁺.

c) Synthesis of3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethoxy)propanoic acid

In a 25-mL round bottom flask, ethyl3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethoxy)propanoate(0.40 g, 0.83 mmol) was dissolved in THF (4 mL)-water (4 rnL) at rt.Lithium hydroxide monohydrate (0.174 g, 4.1 minol) was added to theabove solution and the reaction mixture was stirred at rt for 18 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure and the residue obtained was diluted with water.The aqueous solution was acidified with 2N HCl and extracted with ethylacetate (10 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was purified by preparative HPLC to give the titlecompound (0.099 g, 26.5%) as pale yellow solid. 1H NMR (400 MHz,DMSO-d₆, 60° C.): δ 7.80-7.78 (m, 3H), 7.52 (d, J=8.0 Hz, 2H), 7.36-7.18(m, 2H), 7.08-6.93 (m, 3H), 6.65 (t, J=2.4 Hz, 1H), 4.59 (s, 2H), 4.16(br, 3H), 3.74 (m, 4H), 2.28 (t, J=7.2 Hz, 2H), 1.14 (d, J=6.4 Hz, 6H).LCMS (m/z): 452.3 (M+1)⁺. HPLC: 96.88% (210 nm).

Example 202-(3-(2-((4-(Furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)propoxy)aceticacid

a) Synthesis of ethyl 2-(3-hydroxypropoxy) acetate

In a 50-mL round bottom flask, a stirred solution of ethyl 3-diazo-2-oxoproponoate (1.08 ml, 7.77 mmol) was treated with catalytic amount ofrhodium diacetate (0.02 g) under nitrogen atmosphere. The reactionmixture was cooled to 0° C. and propane-1,3-diol (10 mL) was added dropwise at the same temperature. The reaction mixture was stirred at rt for3 days. Upon completion of the reaction (TLC), the reaction mixturequenched with water and extracted with ethyl acetate (100 mL×2). Thecombined organic extract was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue obtained waspurified by silica gel column chromatography and eluting with 50%EtOAc-hexanes afforded the title product (1.10 g, 88%) as clear oil.LCMS (m/z): 163.2 (M+1)⁺.

b) Synthesis of ethyl 2-(3-bromopropoxy) acetate

In a 50-mL round bottom flask, a stirred solution of ethyl2-(3-hydroxypropoxy)acetate (1.0 g, 6.17 mmol) in THF (20 mL) wastreated with PPh₃ (1.93 g, 7.40 mmol) and CBr₄ (3.0 g, 9.25 mmol) at rtunder nitrogen atmosphere. The reaction mixture was stirred at rt for 3h under nitrogen atmosphere. Upon completion of the reaction (TLC), thereaction mixture was quenched with cold water and extracted with ethylacetate (100 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography(elution with 10% EtOAc-hexanes) to afford the title product as clearoil (0.688 g, 50%). LCMS (m/z): 224 (M+1)⁺.

c) Synthesis of ethyl2-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)propoxy)acetate

A solution of 4-(furan-2-yl)-N-(2-hydroxybenzyl)-N-isopropylbenzamide(0.30 g, 0.88 mmol) of example 16c in DMF (5 mL) was treated withpotassium carbonate (0.183 g, 1.3 mmol) and ethyl2-(3-bromopropoxy)acetate (0.22 g, 0.98 mmol) at rt under nitrogenatmosphere. The reaction mixture was heated at 80° C. for 3 h. Uponcompletion of the reaction (TLC), the reaction mixture was filtered andwashed with EtOAc. The combined filtrate was concentrated under reducedpressure. The residue obtained was diluted with cold water (50 mL) andextracted with EtOAc (200 mL). The organic extract was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (elution 30% EtOAc-hexanes) to give the title compound(0.295 g, 70%). LCMS (m/z): 480.3 (M+1)⁺.

d) Synthesis of2-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)propoxy)acetic acid

In a 50-mL round bottom flask, ethyl2-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)propoxy)acetate(0.47 g, 0.98 mmol) was dissolved in THF (5 mL)-water (3 rnL) at rt.Lithium hydroxide monohydrate (0.206 g, 4.9 mmol) was added to the abovesolution and the reaction mixture was stirred at rt for 18 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure and the residue obtained was diluted with coldwater and washed with diethyl ether. The aqueous solution was acidifiedwith 2N HCl and extracted with ethyl acetate (20 mL×3). The combinedorganic extract was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography (elution 100% EtOAc) to give thetitle compound (0.205 g, 46.4%). ¹H NMR (400 MHz, DMSO-d6, 60° C.) δ12.2 (br s, 1H), 7.75-7.73 (m, 3H), 7.48 (d, J=8.0 Hz, 2H), 6.99-6.95(m, 3H), 6.61-6.60 (m, 1H), 4.53 (s, 2H), 4.12-4.08 (m, 3H), 4.0 (s,2H), 3.68 3.61 (m, 2H), 2.05-1.94 (m, 2H), 1.1 (m, J=6.4 Hz, 6H). LCMS(m/z): 452.2 (M+1)⁺. HPLC=96.27% (210 nm).

Example 216-(2-((4-(Furan-2-yl)-N-(2-methoxyethyl)benzamido)methyl)phenoxy)hexanoicacid

a) Synthesis of 4-(furan-2-yl)benzoic acid

In a 100-mL resealable reaction tube, 4-iodobenzoic acid (10.0 g, 40.03mmol) and furan-2-ylboronic acid (8.95 g, 80.06 mmol) were dissolved indegassed DMF (250 mL) and water (50 mL) at rt under nitrogen atmosphere.Pd(PPh₃)₄ (4.65 g, 3.99 mmol), K₂CO₃ (16.6 g, 120.09 mmol) weresequentially added to the above solution under nitrogen atmosphere. Theresulting mixture was degassed by purging argon gas for 15 min, andreaction mixture was heated to 90° C. until completion of the reaction(TLC). The reaction mixture was cooled to rt, diluted with cold waterand washed with ethyl acetate (3×30 mL).The aqueous layer was separatedand acidified to pH 3 with concentrated HCl, before extracting withEtOAc (100 mL×2). The combined extract was washed with brine andconcentrated under reduced pressure to get title compound (6.92 g, 92%)as light yellow solid. LCMS (m/z): 187 (M−1)⁺.

b) Synthesis of ethyl6-(2-(((2-methoxyethyl)amino)methyl)phenoxy)hexanoate

In a 100-mL round bottom flask, 2-methoxyethanamine (0.62 g, 8.3 mmol)was added to solution of ethyl 6-(2-formylphenoxy)hexanoate (2.0 g, 7.5mmol) of example 1(a) in 1,2-dichloroethane (30 mL) at rt under nitrogenatmosphere. AcOH (3 mL) was added dropwise to the above solution at rt(exothermic). The reaction mixture was stirred at rt for 2 h undernitrogen atmosphere. Sodium borohydride (0.54 g, 14.6 mmol) was added inportions to the above reaction mixture at rt under nitrogen atmosphere.The reaction mixture was stirred at rt for further 1 h under nitrogenatmosphere. The reaction mixture was quenched by addition of saturatedsodium carbonate solution and extracted with dichloromethane. Thedichloromethane layer was washed with brine and dried over anhydrousNa₂SO₄. The solution was concentrated under reduced pressure to give thetitle compound (2.58 g) which was used in the next step without furtherpurification. LCMS (m/z): 324.2 (M+1)⁺.

c) Synthesis of ethyl6-(2-((4-(furan-2-yl)-N-(2-methoxyethyl)benzamido)methyl)phenoxy)hexanoate

In a 50-mL round bottom flask, a stirred solution of ethyl6-(2-(((2-methoxyethyl)amino)methyl)phenoxy)hexanoate (0.50 g, 1.47mmol) in DMF (10 mL) was treated sequentially with 4-(furan-2-yl)benzoicacid (0.304 g, 1.62 mmol) EDCI.HCl (0.330 g, 1.56 mmol) Et₃N (0.3 mL,2.15 mmol) and HOBt (0.231 g, 1.7 mmol) at rt under nitrogen atmosphere.The reaction mixture was stirred at rt for 16 h under nitrogenatmosphere. Upon completion of the reaction (TLC), the reaction mixturewas diluted with cold water and extracted with ethyl acetate (50 mL×3).The combined organic extract was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue obtained waspurified by silica gel column chromatography (elution 50% EtOAc-hexanes)to afford the title compound (0.646 g, 89.2%) as clear oil. LCMS (m/z):494.3 (M+1)⁺.

d) Synthesis of6-(2-((4-(furan-2-yl)-N-(2-methoxyethyl)benzamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, ethyl6-(2-((4-(furan-2-yl)-N-(2-methoxyethyl)benzamido)methyl)phenoxy)hexanoate(0.50 g, 1.01 mmol) was dissolved in THF (5 mL)-water (3 ml.) at rt.Lithium hydroxide monohydrate (0.212 g, 5.0 mmol) was added to the abovesolution and the reaction mixture was stirred at rt for 12 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure and the residue obtained was diluted with water.The aqueous solution washed with diethyl ether and acidified with 2NHCl. The solid precipitated was filtered, washed with n-pentane anddried under reduced pressure to give title compound (0.179 g, 38.13%).¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 12.06-11.32 (br, 1H), 7.81-7.67 (m,3H), 7.45 (d, J=8.0 Hz, 2H), 7.27-7.23 (m, 2H), 7.06-6.89 (m, 3H), 6.60(dd, J=3.6, 2.0 Hz, 1H), 4.63 (br s, 2H), 3.98 (br, 2H), 3.46 (s, 3H),2.21 (t, J=7.2 Hz, 2H), 1.71 (br, 2H), 1.56 (m, 2H), 1.42 (br, 2H). LCMS(m/z): 466.1 (M+1)⁺. HPLC: 97.81% (210 nm).

Example 226-((3-((4-(Furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-2-yl)oxy)hexanoicacid

a) Synthesis of ethyl 6-((3-formylpyridin-2-yl)oxy)hexanoate

In a 50-mL round bottom flask, a stirred solution of2-hydroxynicotinaldehyde (1.5 g, 12.19 mmol) in DMF (30 mL), was treatedwith potassium carbonate (5.0 g, 36.58 mmol) and ethyl 6-bromohexanoate(2.99 g, 13.41 mmol) at rt under nitrogen atmosphere. The reactionmixture was stirred at rt for 4 h. Upon completion of the reaction(TLC), the reaction mixture was diluted with cold water and extractedwith ethyl acetate (50 mL×2). The combined organic extract was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (elution 10% EtOAc-hexanes) to give title compound (0.297g, 9.2%) as the clear oil. ¹H NMR (300 MHz, CDCl₃): δ 10.38 (s, 1H),8.36-8.34 (m, 1H), 8.09 (dd, J=7.5, 2.1 Hz, 1H), 7.00-6.96 (m, 1H), 4.44(t, J=13.2, 6.6 Hz, 2H), 4.17-4.08 (m, 2H), 2.35 (t, J=13.2, 7.2 Hz,2H), 1.90-1.85 (m, 2H) 1.77-1.65 (m, 2H), 1.56-1.46 (m, 2H), 1.24 (t,J=7.2 Hz, 3H). LCMS (m/z): Desired mass peak not observed.

b) Synthesis of ethyl6-((3-((isopropylamino)methyl)pyridin-2-yl)oxy)hexanoate

In a 50-mL round bottom flask, a stirred solution of ethyl6-((3-formylpyridin-2-yl)oxy)hexanoate (300 mg, 1.13 mmol) in ethanol(10 mL) was treated with isopropyl amine (200 mg, 3.39 mmol) and aceticacid (0.3 mL) at rt under nitrogen atmosphere. The mixture stirred at rtfor 6 h under nitrogen atmosphere. Sodium borohydride (85.4 mg, 2.26mmol) was added to the above reaction mixture at rt under nitrogenatmosphere. The resulting mixture was stirred for further 3 h at rt.Upon completion of the reaction (TLC) the reaction mixture was quenchedwith saturated NaHCO₃ and extracted with ethyl acetate (50 mL×2). Thecombined organic extract was washed with water, brine, dried overanhydrous Na₂SO₄. The solution was concentrated under reduced pressureto afford the title compound (310 mg) as yellow oil. The product wasused directly in the next step without any further purification. LCMS(m/z): 309.2 (M+1)⁺.

c) Synthesis of ethyl6-((3-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-2-yl)oxy)hexanoate

In a 25-mL round bottom flask, a stirred solution of ethyl6-((3-((isopropylamino)methyl)pyridin-2-yl)oxy)hexanoate (0.301 g, 0.974mmol) in DMF (10 mL) was treated with 4-(furan-2-yl)benzoic acid (0.210g, 1.07 mmol), EDCI.HCl (0.372 g, 1.94 mmol), HOBt (0.264 g, 1.94 mmol)and triethylamine (0.412 g, 4.07 mmol) at rt under nitrogen atmosphere.The reaction mixture was stirred at rt for 2 days. Upon completion ofthe reaction (TLC), the reaction mixture diluted with cold water andextracted with ethyl acetate (25 mL×2). The combined organic extract waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue obtained was purified by silica gel columnchromatography (elution 30% EtOAc-hexanes) to give title compound (0.251g, 53.9%) as off-white solid. LCMS (m/z): 479.2 (M+1)⁺.

d) Synthesis of6-((3-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-2-yl)oxy)hexanoicacid

In a 25-mL round bottom flask, ethyl6-((3-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-2-yl)oxy)hexanoate(250 mg, 0.523 mmol) was dissolved in THF (10 mL)-water (10 ml_) mixtureat rt. Lithium hydroxide monohydrate (109 mg, 2.61 mmol) was added tothe above solution and the reaction mixture was stirred at rt for 18 h.Upon completion of the reaction (TLC), the reaction mixture wasconcentrated under reduced pressure. The residue obtained was dilutedwith cold water and acidified with 2N HCl, before extracting with ethylacetate (10 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was purified by silica gel column chromatography(elution, 50% EtOAc-hexanes) to give title compound (129 mg, 55%) a paleyellow gummy liquid. 1′H NMR (400 MHz, DMSO-d₆, 60° C.) δ 12.02 (s, 1H),8.08-7.96 (m, 1H), 7.80 (br, 2H), 7.60-7.50 (m, 3H), 7.06 (br, 1H), 6.98(dd, J=7.2, 5.2 Hz, 1H), 6.69-6.57 (m, 1H), 4.44 (s, 2H), 4.33 (m, 2H),4.05 (br, 1H), 2.25 (br s, 2H), 1.79-1.76 (m, 2H), 1.60-1.55 (m, 2H),1.49-1.45 (m, 2H), 1.08 (br s, 6H). LCMS (m/z): 451.2 (M+1)⁺. HPLC:96.87% (210 nm).

Example 236-(2-((4-(Furan-2-yl)-N-isopropylphenylsulfonamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl6-(2-((4-bromo-N-isopropylphenylsulfonamido)methyl)phenoxy) hexanoate

In a 25-mL round bottom flask, a stirred solution of ethyl6-(2-((isopropylamino)methyl)phenoxy)hexanoate (500 mg, 1.62 mmol) inpyridine (10 mL) was treated with 4-bromobenzene-1-sulfonyl chloride(496 mg, 1.95 mmol) at rt under nitrogen atmosphere. The reactionmixture was stirred at rt for 12 h. Upon completion of the reaction(TLC) the reaction mixture was quenched with cold water and extractedwith ethyl acetate (25 mL×2). The combined organic extract was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by silica gel (60-120 mesh)column chromatography (elution 20% EtOAc-hexanes) to give title compound(301 mg, 35%) as yellow oil. LCMS (m/z): 547.9 (M+Na)⁺.

b) Synthesis of ethyl6-(2-((4-(furan-2-yl)-N-isopropylphenylsulfonamido)methyl)phenoxy)hexanoate

In a 50-mL resealable reaction tube, ethyl6-(2-((4-bromo-N-isopropylphenylsulfonamido)methyl) phenoxy)hexanoate(300 mg, 0.57 mmol) was dissolved in degassed solvent mixture of DME (7mL), water (7 mL) and ethanol (2 mL) at rt under nitrogen atmosphere.Pd(PPh₃)₄ (19.7 mg, 0.017 mmol), furan-2-ylboronic acid (127 mg, 1.14mmol) and Na₂CO₃ (181 mg, 1.71 mmol) were sequentially added to theabove solution under nitrogen atmosphere. The resulting mixture wasdegassed by purging argon gas for 15 min. The reaction mixture washeated to 90° C. and stirred at same temperature until completion of thereaction (TLC). The reaction mixture was cooled to rt, diluted with coldwater and extracted with ethyl acetate (30 mL×3). The combined EtOAcextract was washed with brine and concentrated under reduced pressure.The residue obtained was purified by silica gel column chromatography(elution 30% EtOAc-hexanes) to afford the title product (278 mg, 95%) asclear oil. LCMS (m/z): 514.3 (M+1)⁺.

c) Synthesis of6-(2-((4-(furan-2-yl)-N-isopropylphenylsulfonamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, ethyl6-(2-((4-(furan-2-yl)-N-isopropylphenylsulfonamido)methyl)phenoxy)hexanoate (270 mg, 0.526 mmol) was dissolvedin THF (10 m)), water (10 mL) and ethanol (2 mL) mixture at rt. Lithiumhydroxide monohydrate (122 mg, 2.92 mmol) was added to the abovesolution and the reaction mixture was stirred at rt for 12 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure and residue obtained was diluted with cold water.The aqueous solution was acidified with 2N HCl and extracted with ethylacetate (10 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was washed with n-pentane to afford the title compound(186 mg, 70.1%) as off white solid. ¹H NMR (300 MHz, DMSO-d₆, 60° C.): δ11.98 (s, 1H), 8.10-7.73 (m, 5H), 7.55-7.32 (m, 1H), 7.32-7.10 (m, 2H),7.01-6.84 (m, 2H), 6.66 (dd, J=3.6, 1.8 Hz, 1H), 4.33 (s, 2H), 4.12-4.05(m, 1H), 3.97 (t, J=6.4 Hz, 2H), 2.19 (t, J=7.2 Hz, 2H), 1.74-1.70 (m,2H), 1.53-1.51 (m, 2H), 1.43-1.41 (m, 2H), 0.83 (d, J=6.6 Hz, 6H). LCMS(m/z): 508.5 (M+1)⁺. HPLC: 94.32% (210 nm).

Example 24 6-(2-((4-(Furan-2-yl)benzamido)methyl)phenoxy)hexanoic acid

a) Synthesis of (E)-methyl 6-(2-((hydroxyimino)methyl) phenoxy)hexanoate

In a 100-mL round bottom flask, a stirred solution of ethyl6-(2-formylphenoxy)hexanoate (2.0 g, 7.5 mmol) in water (40 mL), wastreated aqueous hydroxyl amine (1.25 g, 37.8 mmol) at rt. The resultingmixture was heated at 100° C. for 30 min to give an off whitesuspension. The suspension was allowed to cool to ambient temperatureand then further cooled in an ice-bath. The solid formed was filtered,washed with water and dried under reduced pressure to afford the titlecompound (1.81 g, 86.8%) as white solid. ¹H-NMR (300 MHz, DMSO-d₆):δ11.18 (s, 1H), 8.27 (s, 1H), 7.65-7.59 (m, 1H), 7.35-7.29 (m, 1H),7.04-7.00 (d, J=8.1 Hz, 1H), 6.94-6.89 (t, J=7.8 Hz, 1H), 4.06-3.96 (m,4H), 2.31-2.27 (t, J=14.4 Hz, 2H), 1.76-1.67 (m, 2H), 1.62-1.52 (m, 2H),1.46-1.38 (m, 2H), 1.17 (t, J=7.2 Hz, 3H). LCMS (m/z): 279.3 (M+1)⁺.

b) Synthesis of ethyl 6-(2-(aminomethyl)phenoxy)hexanoate

In a 100-mL round bottom flask, a stirred solution of (E)-methyl6-(2-((hydroxyimino)methyl)phenoxy)hexanoate (1.30 g, 4.6 mmol) inethanol (20 mL) was treated with 10% palladium on activated carbon (0.30g) at rt under nitrogen atmosphere. The resulting suspension washydrogenated (balloon) at rt for 12 h. Upon completion of the reaction(TLC), reaction mixture was filtered over a celite bed and filtrated wasconcentrated under reduced pressure to afford the title compound (1.10g, 89.43%) as clear oil. LCMS (m/z): 266.3 (M+1)⁺.

c) Synthesis of ethyl6-(2-((4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoate

In a 50-mL round bottom flask, EDCI.HCl (0.25 g, 1.3 mmol) andtriethylamine (2.0 mL, 1.6 mmol) were sequentially to a solution ofmethyl 6-(2-(amino methyl)phenoxy)hexanoate (0.3 g, 1.1 mmol),4-(furan-2-yl)benzoic acid (0.21 g, 1.1 mmol) and HOBt (0.180 g, 1.3mmol) in dimethylformamide (10 mL) at rt under nitrogen atmosphere. Thereaction mixture was stirred at rt for 16 h under nitrogen atmosphere.The reaction mixture was concentrated under reduced pressure. Theresidue obtained was purified by silica gel (60-120 mesh) columnchromatography (elution 50% EtOAc-hexanes) to give the title compound(0.243 g, 50.7%). LCMS (m/z): 458.2 (M+Na)⁺.

d) Synthesis of 6-(2-((4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid

A solution of ethyl6-(2-((4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoate (0.25 g, 0.57mmol) in THF (10 mL) and water (5 mL) was treated with lithium hydroxidemonohydrate (0.241 g, 5.7 mmol) at rt. The reaction mixture was stirredat rt for 12 h. Upon completion of reaction (TLC), the reaction mixturewas concentrated under reduced pressure and residue obtained was dilutedwith water. The aqueous solution was washed with diethyl ether andacidified with 1N HCl, when solid precipitated. The solid was filtered,washed with water, n-pentane and dried under reduced pressure to affordthe title compound (0.099 g, 42.7%). ¹H NMR (300 MHz, DMSO-d₆, 60° C.):δ 11.99 (s, 1H), 8.83 (t, J=5.8 Hz, 1H), 8.03-7.87 (m, 2H), 7.86-7.71(m, 3H), 7.24-7.11 (m, 2H), 7.09 (d, J=3.4 Hz, 1H), 6.96 (d, J=8.1 Hz,1H), 6.87 (t, J=7.4 Hz, 1H), 6.63 (dd, J=3.4, 1.8 Hz, 1H), 4.45 (d,J=5.8 Hz, 2H), 3.99 (t, J=6.2 Hz, 2H), 2.21 (t, J=7.1 Hz, 2H), 1.76-1.71(m, 2H), 1.57-1.44 (m, 4H). LCMS (m/z): 430.1 (M+Na)⁺. HPLC: 95.46% (210nm).

Example 256-(4-Bromo-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl 6-(4-bromo-2-formylphenoxy)hexanoate

In a 50-mL round bottom flask, a stirred solution of substituted5-bromo-2-hydroxybenzaldehyde (5.0 g, 24.8 mmol) in DMF (30 mL), wastreated with potassium carbonate (10.26 g, 74.4 mmol) and ethyl6-bromohexanoate (6.6 g, 29.8 mmol) at rt under nitrogen atmosphere. Thereaction mixture was heated at 90° C. for 4 h. Upon completion of thereaction (TLC) the reaction mixture was cooled to rt, diluted with coldwater and extracted ethyl acetate (250 mL×2). The combined organicextract was washed with brine and dried over anhydrous Na₂SO₄. Thesolution was concentrated under reduced pressure to give the titlecompound (7.97 g, 94%) as yellow oil. LCMS (m/z): 343.2 (M+1)⁺.

b) Synthesis of ethyl 6-(2-(aminomethyl)-4-bromophenoxy)hexanoate

In a 100-mL round bottom flask, a stirred solution of substituted ethyl6-(4-bromo-2-formylphenoxy)hexanoate (2.0 g, 5.84 mmol) in1,2-dichloroethane (50 mL), was treated with isopropylamine (0.37 g,6.26 mmol) and acetic acid (2.5 g, 41.6 mmol) at rt. The mixture wasstirred at rt for 30 min and treated with NaBH(OAc)₃ (2.70 g, 12.73mmol) at rt under nitrogen atmosphere. The reaction mixture was stirredat rt for 3 h. Upon completion of the reaction (TLC) the reactionmixture was quenched with saturated NaHCO₃ and extracted with ethylacetate (50 mL×2). The combined organic extract was washed with water,brine and dried over anhydrous Na₂SO₄. The solution was concentratedunder reduced pressure to afford the title compound (1.52 g) as yellowoil, which was used in the next step without further purification. LCMS(m/z): 386.1 (M+1)⁺.

c) Synthesis of ethyl6-(4-bromo-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate

In a 25-mL round bottom flask, a stirred solution of6-(4-bromo-2-((isopropylamino)methyl)phenoxy)hexanoate (500 mg, 1.29mmol) in DMF (15 mL), was treated sequentially with4-(furan-2-yl)benzoic acid (267 mg, 1.42 mmol), EDCI.HCl (492 mg, 2.58mmol), HOBt (350 mg, 2.58 mmol) and triethylamine (546 mg, 5.6 mmol) atrt under nitrogen atmosphere. The reaction mixture was stirred at rt for18 h under nitrogen atmosphere. Upon completion of the reaction (TLC),the reaction mixture was diluted with cold water and extracted withethyl acetate (25 mL×2). The combined organic extract was washed withwater, brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was purified by silica gel columnchromatography (elution 15% EtOAc-hexanes) to give the title compound(681 mg, 94.7%) as clear oil. LCMS (m/z): 557.2 (M+1)⁺.

d) Synthesis of6-(4-bromo-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, a stirred solution ethyl6-(4-bromo-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate(500 mg, 0.899 mmol) was dissolved in THF (10 mL)-water (10 mL)-EtOH (2mL) at rt. Lithium hydroxide monohydrate (188 mg, 4.48 mmol) was addedto the above solution and the reaction mixture was stirred at rt for 5h. Upon completion of the reaction (TLC), the reaction mixture wasconcentrated under reduced pressure and the residue obtained was dilutedwith water. The aqueous solution was acidified with 2N HCl and extractedwith ethyl acetate (10 mL×2). The combined organic extract was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue obtained was washed repeatedly with n-pentane togive the title compound (349 mg, 73.7%) as clear oil. 11H NMR (400 MHz,DMSO-d₆, 60° C.): δ 11.80 (s, 1H), 7.81-7.75 (m, 3H), 7.44 (d, J=7.6 Hz,2H), 7.37 (dd, J=8.8, 2.4 Hz, 1H), 7.31 (s, 1H), 7.00 (d, J=3.2 Hz, 1H),6.95 (d, J=8.8 Hz, 1H), 6.66-6.58 (m, 1H), 4.51 (s, 2H), 4.17 (br, 1H),4.02 (t, J=6.4 Hz, 2H), 3.62 (d, J=6.4 Hz, 2H), 2.24 (t, J=7.3 Hz, 2H),1.79-1.75 (m, 4H), 1.61-1.58 (m, 2H), 1.52-1.40 (m, 2H), 1.11 (d, J=6.4Hz, 6H). LCMS (m/z): 527.9 (M+1)⁺. HPLC: 95.01% (210 nm).

Example 266-(4-Fluoro-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid

The title compound (190 mg) was prepared starting from5-fluoro-2-hydroxybenzaldehyde (1.0 g, 7.14 mmol) using the procedure ofExample-25. ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 7.77-7.74 (m, 3H), 7.48(d, J=7.6 Hz, 2H), 7.01-6.99 (m, 4H), 6.61 (dd, J=3.2, 1.6 Hz, 1H), 4.52(s, 2H), 4.15 (br, 1H), 4.00 (t, J=6.4 Hz, 2H), 2.24 (t, J=7.2 Hz, 2H),1.81-1.70 (m, 2H), 1.62-1.58 (m, 2H), 1.49-1.47 (m, 2H), 1.11 (d, J=6.6Hz, 6H). LCMS (m/z): 468.2 (M+1)⁺. HPLC: 96.75% (210 nm).

Example 276-(2-((4-(Furan-2-yl)-N-isopropylbenzamido)methyl)-4-methylphenoxy)hexanoicacid

The title compound (350 mg) was prepared from2-hydroxy-5-methylbenzaldehyde (2.5 g, 18.38 mmol) using the procedureof Example-25. ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 11.79 (s, 1H),7.79-7.69 (m, 3H), 7.46 (d, J=7.6 Hz, 2H), 7.08-6.94 (m, 3H), 6.84 (d,J=8.0 Hz, 1H), 6.61 (dd, J=3.2, 1.6 Hz, 1H), 4.50 (s, 2H), 4.15 (br,1H), 3.96 (t, J=6.4 Hz, 2H), 2.25 (m, 5H), 1.78-1.70 (br, 2H), 1.60-1.55(m, 2H), 1.47-1.42 (m, 2H), 1.11 (d, J=6.4 Hz, 6H). LCMS (m/z): 464.3(M+1)⁺. HPLC: 97.47% (210 nm).

Example 286-(2-((4-(Furan-2-yl)-N-isopropylbenzamido)methyl)-4-methoxyphenoxy)hexanoicacid

a) Synthesis of 2-hydroxy-5-methoxybenzaldehyde

In a 250-mL round bottom flask, a stirred solution of2,5-dimethoxybenzaldehyde (5.0 g, 30.02 mmol) was dissolved in DCM (50mL). Aluminum chloride (18.2 g, 136.8 mmol) was added to the abovesolution at rt under nitrogen atmosphere. The reaction mixture wasstirred at rt for 12 h. Upon completion of the reaction (TLC), thereaction mixture was diluted with cold water and extracted with DCM (100mL×2). The combined organic extract was washed with brine andconcentrated under reduced pressure to get title compound (4.51 g, 98%)as yellow oil. LCMS (m/z): 152.1 (M+1)⁺.

b) Synthesis of6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)-4-methoxyphenoxy)hexanoic acid

The title compound (230 mg) was prepared from2-hydroxy-5-methoxybenzaldehyde (2.5 g, 16.44 mmol) using the procedureof Example-25. ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ 11.81 (s, 1H), 7.75(d, J=6.4 Hz, 3H), 7.45 (d, J=7.6 Hz, 2H), 6.99 (d, J=3.2 Hz, 1H), 6.89(d, J=8.8 Hz, 1H), 6.82-6.72 (m, 2H), 6.61 (m, 1H), 4.51 (s, 2H), 4.14(br, 1H), 3.94 (t, J=6.1 Hz, 2H), 3.72 (s, 3H), 2.23 (t, J=7.2 Hz, 2H),1.73 (br, 2H), 1.60-1.57 (m, 2H), 1.50-1.38 (m, 2H), 1.11 (d, J=6.4 Hz,6H). LCMS (m/z): 480.5 (M+1)⁺. HPLC: 95.33% (210 nm).

Example 296-(4-Cyano-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl6-(4-cyano-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate

In a 50-mL resealable reaction tube, ethyl6-(4-bromo-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate(500 mg, 0.879 mmol) from example 25c was dissolved in degassed DMA (15mL) at rt under nitrogen atmosphere. Pd₂(dba)₃ (21.0 mg, 0.023 mmol), Znpowder (0.126 g, 0.002 mmol) and dppf (14.9 mg, 0.027 mmol) and Zn(CN)₂(62.6 mg, 0.51 mmol) were sequentially added to the above solution undernitrogen atmosphere. The resulting mixture was degassed by purging argongas for 15 min. The reaction mixture was heated to 100° C. and stirredat same temperature until completion of the reaction (TLC). The reactionmixture was cooled to rt, diluted with cold water and extracted withethyl acetate (3×30 mL). The combined organic extract was washed withbrine and concentrated under reduced pressure. The residue obtained waspurified by silica gel column chromatography (gradient elution, 10-15%EtOAc-hexanes) to afford the title compound (361 mg, 81.8%) as paleyellow solid. LCMS (m/z): 503.2 (M+1)⁺.

b) Synthesis of6-(4-cyano-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid

In a 25-mL round bottom flask, ethyl6-(4-cyano-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate(0.30 g, 0.597 mmol) was dissolved in THF (4 mL)-water (4 m) mixture atrt. Lithium hydroxide monohydrate (0.125 g, 2.988 nmol) was added to theabove solution and the reaction mixture was stirred at rt for 18 h. Uponcompletion of the reaction (TLC), the reaction mixture was concentratedunder reduced pressure; residue obtained was diluted with water andacidified with 2N HCl. The aqueous solution was extracted with ethylacetate (10 mL×2). The combined organic extract was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue obtained was washed with n-pentane and dried under reducedpressure to give the title compound (0.150 g, 53%) as pale yellow solid.1H NMR (400 MHz, DMSO-d₆, 60° C.) δ 11.80 (s, 1H), 7.77-7.75 (m, 3H),7.70 (dd, J=8.4, 2.0 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.51 (d, J=7.6 Hz,2H), 7.17 (d, J=8.8 Hz, 1H), 7.00 (d, J=3.2 Hz, 1H), 6.62 (dd, J=3.6,1.6 Hz, 1H), 4.52 (s, 2H), 4.14 (t, J=6.4 Hz, 2H), 2.24 (t, J=7.2 Hz,2H), 1.81-178 (m, 2H), 1.62-159 (m, 2H), 1.50-1.47 (m, 2H), 1.12 (d,J=6.4 Hz, 6H). LCMS (m/z): 475.2 (M+1)⁺. HPLC: 95.98% (210 nm).

Example 306-(2-((4-(furan-2-yl)-N-(2,2,2-trifluoroethyl)benzamido)methyl)phenoxy)hexanoicacid

a) Synthesis of ethyl6-(2-(((2,2,2-trifluoroethyl)amino)methyl)phenoxy)hexanoate

To a stirred solution of ethyl 6-(2-formylphenoxy)hexanoate (0.50 g,1.89 mmol) in 1,2-dichloroethane (50 mL), 2,2,2-trifluoroethanamine(0.21 g, 2.12 mmol) and acetic acid (0.85 g, 124.74 mmol) were added atrt under nitrogen atmosphere. The mixture was stirred at rt for 30 minand treated with NaBH(OAc)₃ (0.9 g, 12.47 mmol) under nitrogenatmosphere. The reaction mixture was stirred at rt for 3 h. Uponcompletion of the reaction (TLC), the reaction mixture was quenched withsaturated NaHCO₃ and extracted with ethyl acetate (50 mL×2). Thecombined organic extract was washed with water, brine, dried overanhydrous Na₂SO₄. The solution was concentrated under reduced pressureto give the title compound (0.61 g), which was used in the next stepwithout further purification. LCMS (m/z): 348.3 (M+1)⁺.

b) Synthesis of ethyl6-(2-((4-(furan-2-yl)-N-(2,2,2-trifluoroethyl)benzamido)methyl)phenoxy)hexanoate

In a 50-mL round bottom flask, a stirred solution ethyl6-(2-(((2,2,2-trifluoroethyl)amino)methyl)phenoxy)hexanoate (0.55 g,1.58 mmol) in DCM (30 mL) was treated with 4-(furan-2-yl)benzoylchloride (0.3 g, 1.4 mmol) [prepared by reaction of4-(furan-2-yl)benzoic acid (0.3 g) and thionyl chloride (2 mL) at rt for12 h] and Et₃N (0.431 mL, 3.17 mmol) at rt under nitrogen atmosphere.The reaction mixture was stirred at rt for 2 h under nitrogenatmosphere. Upon completion of the reaction (TLC), the reaction mixturewas diluted with cold water (10 mL) and extracted with DCM (30 mL×2).The combined organic extract was washed with aqueous NaHCO₃, brine anddried over anhydrous Na₂SO₄. The solution was concentrated under reducedpressure and residue obtained was purified by silica gel columnchromatography (elution 50% EtOAc-hexanes) to give title compound (0.351g, 42.9%). LCMS (m/z): 540.2 (M+Na)⁺.

c) Synthesis of6-(2-((4-(furan-2-yl)-N-(2,2,2-trifluoroethyl)benzamido)methyl)phenoxy)hexanoic acid

A stirred solution of ethyl6-(2-((4-(furan-2-yl)-N-(2,2,2-trifluoroethyl)benzamido)methyl)phenoxy)hexanoate(0.10 g, 0.193 mmol) in THF (5 mL), EtOH (3 mL) and water (2 mL) wastreated with lithium hydroxide monohydrate (0.04 g, 0.96 mmol) at rt.The mixture was stirred at 90° C. for 3 h. Upon completion of thereaction (TLC), the solvent was removed under reduced pressure. Theresidue obtained was washed with EtOAc and n-pentane. The residue wasdissolved in water and the solution acidified with 2 N HCl. The aqueoussolution was extracted with EtOAc (25 mL×3). The combined organicextract was dried over anhydrous Na₂SO₄, and concentrated under reducedpressure to give the title compound (0.025 g, 62.8%). ¹H NMR (400 MHz,DMSO-d₆, 80° C.): δ 7.75 (d, J=8.0 Hz, 3H), 7.46 (d, J=8.0 Hz, 2H), 7.26(t, J=7.6 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 7.02-6.87 (m, 3H), 6.60 (dd,J=3.2, 1.6 Hz, 1H), 4.68 (s, 2H), 4.18 (q, J=9.6 Hz, 2H), 3.95 (t, J=6.4Hz, 2H), 2.01 (br t, J=7.2 Hz, 2H), 1.69-1.65 (m, 2H), 1.56-1.50 (m,2H), 1.39-1.34 (m, 2H). LCMS (m/z): 540.2 (M+1)⁺. HPLC: 95.11% (210 nm).

Example 316-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)hexanoic acid

a) Synthesis of ethyl 6-(2-((methylamino)methyl)phenoxy)hexanoate

In a 50-mL round bottom flask, a solution of methyl amine hydrochloride(0.515 g, 7.62 mmol) in MeOH (15 mL) was treated with Et₃N (1.03 mL, 7.5mmol) at rt. The mixture was stirred at rt for 15 min and treated with asolution ethyl 6-(2-formylphenoxy)hexanoate (0.5 g, 1.89 mmol) in MeOH(15 mL) at rt under nitrogen atmosphere. The resulting mixture wasstirred at rt for 1 h. The mixture was cooled to 0° C. and NaBH₄ (0.037g, 0.99 mmol) was added in portions at rt. The reaction mixture wasstirred at rt for 1 h. Upon completion of the reaction (TLC), thereaction mixture was concentrated under reduced pressure. The residueobtained was diluted with cold water and extracted with EtOAc (30 mL×2).The combined organic extract was washed with brine and dried overanhydrous Na₂SO₄. The solution was concentrated under reduced pressureto afford the title compound (0.408 g), which was used in the next stepwithout further purification. LCMS (m/z): 280.1 (M+1)⁺.

b) Synthesis of ethyl6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy) hexanoate

In a 50-mL round bottom flask, a stirred solution of ethyl6-(2-((methylamino)methyl)phenoxy)hexanoate (0.4 g, 1.43 mmol) and4-(furan-2-yl)benzoic acid (0.323 g, 1.72 mmol) in DMF (20 mL) wastreated with EDCI.HCl (0.546 g, 2.86 mmol), HOBt (0.388 g, 2.86 mmol)and Et₃N (0.778 mL, 5.72 mol) at rt under nitrogen atmosphere. Thereaction mixture was stirred at rt for 12 h under nitrogen atmosphere.Upon completion of reaction (TLC), the reaction mixture was diluted withcold water, and extracted with EtOAc (30 mL×2). The combined organicextract was washed with saturated NaHCO₃, brine and dried over anhydrousNa₂SO₄. The solution was concentrated under reduced pressure and residueobtained was purified by silica gel column chromatography (elution, 20%EtOAc-hexanes) to yield the title compound (0.399 g, 62.1%). LCMS (m/z):472.1 (M+Na)⁺.

c) Synthesis of6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)hexanoic acid

To a stirred solution of ethyl6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy) hexanoate (0.200g, 0.44 mmol) in THF (10 mL), EtOH (8 mL) and water (5 mL), was treatedwith lithium hydroxide monohydrate (0.092 g, 2.20 mmol) at rt. Themixture was stirred at 90° C. for 3 h. Upon completion of reaction(TLC), the reaction mixture was concentrated under reduced pressure. Theresidue was washed with EtOAc, diluted with cold water and acidifiedwith 2N HCl. The aqueous layer was extracted with EtOAc (25 mL×3). Thecombined organic extract was washed with brine and dried over anhydrousNa₂SO₄. The solution was concentrated under reduced pressure to give thetitle compound (0.110 g, 59.5%). ¹H NMR (400 MHz, DMSO-d₆, 60° C.): δ11.76 (s, 1H), 7.79-7.68 (m, 3H), 7.47 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.6Hz, 1H), 7.19 (d, J=7.2 Hz, 1H), 7.04-6.93 (m, 3H), 6.60 (br, 1H), 4.58(br s, 2H), 3.98 (br, 2H), 2.90 (s, 3H), 2.20 (t, J=7.2 Hz, 2H),1.72-1.63 (m, 2H), 1.62-1.51 (m, 2H), 1.48-1.29 (m, 2H). LCMS (m/z):422.0 (M+1)⁺. HPLC: 96.89% (210 nm).

Example 9 Pharmacokinetics

In this example, the PK profile of several PPARδ agonists disclosedherein in male CD-1 mice or Wistar rats was determined. Similar methodscan be used to analyze other compounds provided herein.

Compounds 12 and 176 were dissolved in 2% dimethylacetamide (DMA) and20% 2-hydroxypropyl-beta-cyclodextrin (HPβCD) q.s. Compound 245 andGW501516 were dissolved in 5% ethanol and 5% solution in purified waterq.s. (quantity sufficient i.e. made up to a final volume of 100% withwater). All compounds were separately administered to CD-1 mice at 3mg/kg iv or 10 mg/kg po. GW501516 was administered to Wistar rats at 3mg/kg (i.v.) or 10 mg/kg (p.o.).

The concentration of the compound in plasma was determined, asillustrated in FIGS. 9A-9E.

Experimental parameters for compound 12 are provided in Tables 2A and2B, with in vitro parameters and data provided in Table 2C.

TABLE 2A Intravenous PK parameters Parameters K_(el) Beta AUC _((0-inf))C₀ V_(z) V_(ss) Cl (hr- T_(1/2) (hr*ng/ (ng/ (L/ (L/ (mL/ MRT 1) (hr)mL) mL) kg) kg) hr/kg) (hr) 3 mg/Kg 3.85 0.18 256.5 1938.2 3.03 1.5811696.3 0.12

TABLE 2B Oral PK parameters AUC_((0-inf)) T_(max) C_(max) T_(1/2) FParameters (hr*ng/mL) (hr) (ng/mL) (hr) % 10 mg/Kg 187.0 0.50 128.7 2.60~22

TABLE 2C In vitro parameters/data Solubility (μM) Kinetic 6Thermodynamic 253 % Parent remained at 15/60 min MLM 59/19 HLM 92/64Potency (cell based) PPAR delta 4.8 EC₅₀ (nM) NHR ptn interaction assay

Experimental parameters for compound 176 are provided in Tables 3A and3B, with in vitro parameters and data provided in Table 3C.

TABLE 3A Intravenous PK parameters Parameters K_(el) Beta AUC _((0-inf))C₀ V_(z) V_(ss) Cl (hr- T_(1/2) (hr*ng/ (ng/ (L/ (L/ (mL/ MRT 1) (hr)mL) mL) kg) kg) hr/kg) (hr) 3 mg/Kg 0.41 1.68 1134.7 7056.5 6.42 1.642643.8 0.47

TABLE 3B Oral PK parameters AUC_((0-inf)) T_(max) C_(max) T_(1/2) FParameters (hr*ng/mL) (hr) (ng/mL) (hr) % 10 mg/Kg 943.8 0.25 1111.72.68 ~25.0

TABLE 3C In vitro parameters/data Solubility (μM) Kinetic 191Thermodynamic 506 % Parent remained at 15/60 min MLM 78/56 HLM 100/73 Potency (cell based) PPAR delta 12.6 EC₅₀ (nM) NHR ptn interaction assayExperimental in vitro parameters and data for compound 237 are providedin Table 4.

TABLE 4 Solubility (μM) Kinetic 146 Thermodynamic  88 % Parent remainedat 15/60 min MLM 88/60 HLM 77/38 Potency (cell based) PPAR delta 11 nMEC₅₀ (nM) NHR ptn interaction assay

Experimental parameters for compound GW501516 administered to maleWistar rats are provided in Tables 5A and 5B, with in vitro parametersand data provided in Table 5C.

TABLE 5A Intravenous PK parameters Parameters K_(el) Beta AUC _((0-inf))C₀ V_(z) V_(ss) Cl (hr- T_(1/2) (hr*ng/ (ng/ (L/ (L/ (mL/ MRT 1) (hr)mL) mL) kg) kg) hr/kg) (hr) 3 mg/Kg 0.09 8.07 9960.0 5277.8 3.58 1.99305.9 4.30

TABLE 5B Oral PK parameters AUC_((0-inf)) T_(max) C_(max) T_(1/2) FParameters (hr*ng/mL) (hr) (ng/mL) (hr) % 10 mg/Kg 35121.0 2.00 6920.06.21 ~100

TABLE 5C In vitro parameters/data Solubility (μM) Kinetic 195Thermodynamic 246 % Parent remained at 15/60 min MLM 93/76 Potency (cellbased) PPAR delta 2 nM EC₅₀ (nM) trans activation

Experimental parameters for compound GW501516 administered to CD-1 miceare provided in Tables 6A and 6B, with in vitro parameters and dataprovided in Table 6C.

TABLE 6A Intravenous PK parameters Parameters K_(el) Beta AUC _((0-inf))C₀ V_(z) V_(ss) Cl (hr- T_(1/2) (hr*ng/ (ng/ (L/ (L/ (mL/ MRT 1) (hr)mL) mL) kg) kg) hr/kg) (hr) 3 mg/Kg 0.11 6.44 11319.1 5560.5 2.46 1.71265.0 4.96

TABLE 6B Oral PK parameters AUC_((0-inf)) T_(max) C_(max) T_(1/2) FParameters (hr*ng/mL) (hr) (ng/mL) (hr) % 10 mg/Kg 30990.7 2.00 3293.35.98 82.1

TABLE 6C In vitro parameters/data Solubility (μM) Kinetic 195Thermodynamic 246 % Parent remained at 15/60 min MLM 93/76 Potency (cellbased) PPAR delta 2 nM EC₅₀ (nM) trans activation

Example 10

The following examples provide physical and in vitro data for variousdifferent exemplary compounds.

Nuclear Hormone Receptor (NHR) Assays Cell Handling:

PathHunter NHR cell lines were expanded from freezer stocks according tostandard procedures. Cells were seeded in a total volume of 20 μL intowhite walled, 384-well microplates and incubated at 37° C. for theappropriate time prior to testing. Assay media containedcharcoal-dextran filtered serum to reduce the level of hormones present.

Agonist Format:

For agonist determination, cells were incubated with sample to induceresponse. Intermediate dilution of sample stocks was performed togenerate 5× sample in assay buffer. 5 μL of 5× sample was added to cellsand incubated at 37° C. or room temperature for 3-16 hours. Final assayvehicle concentration was 1%.

Antagonist Format:

For antagonist determination, cells were pre-incubated with antagonistfollowed by agonist challenge at the EC₈₀ concentration. Intermediatedilution of sample stocks was performed to generate 5× sample in assaybuffer. 5 μL of 5× sample was added to cells and incubated at 37° C. orroom temperature for 60 minutes. Vehicle concentration was 1%. 5 μL of6×EC₈₀ agonist in assay buffer was added to the cells and incubated at37° C. or room temperature for 3-16 hours.

Signal Detection:

Assay signal was generated through a single addition of 12.5 or 15 L(50% v/v) of PathHunter Detection reagent cocktail, followed by a onehour incubation at room temperature. Microplates were read followingsignal generation with a PerkinElmer Envision™ instrument forchemiluminescent signal detection.

Data Analysis:

Compound activity was analyzed using CBIS data analysis suite(ChemInnovation, CA). For agonist mode assays, percentage activity wascalculated using the following formula:

% Activity=100%×(mean RLU of test sample−mean RLU of vehiclecontrol)/(mean MAX control ligand−mean RLU of vehicle control).

For antagonist mode assays, percentage inhibition was calculated usingthe following formula:

% Inhibition=100%×(1−(mean RLU of test sample−mean RLU of vehiclecontrol)/(mean RLU of EC ₈₀ control−mean RLU of vehicle control)).

Note that for select assays, the ligand response produces a decrease inreceptor activity (inverse agonist with a constitutively active target).For those assays inverse agonist activity was calculated using thefollowing formula:

% Inverse Agonist Activity=100%×((mean RLU of vehicle control−mean RLUof test sample)/(mean RLU of vehicle control−mean RLU of MAX control)).

TABLE 7 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 127 467 5.57 44.6 176 421 4.68 12.6 247 447 5.49 10.54 12 447 5.274.8 247 497 6.45 18.8

TABLE 8 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 61 449 5.52 5.9 12 447 5.04 4.8 126 413 4.47 1298.5 127 467 5.5744.6 129 425 3.96 5071.10 130 461 3.03 >10000 237 447 5.49 10.54 132 4014.47 2184.70 151 408 3.85 894.3 135 449 5.31 3151.9 136 450 4.58 351.8134 437 4.80 95.5 133 497 3.67

TABLE 9 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 61 449 5.52 5.9 12 447 5.04 4.8 152 485 5.83 >10000 153 450 4.42206.4 154 453 5.51 21.3 155 450 4.63 26.1 156 456 4.46 142.9 157 4495.82 >10000 158 449 5.60 >10000 160 467 5.75 159 467 5.75

TABLE 10 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 61 449 5.52 5.9 12 447 5.04 4.8 176 421 4.68 12.6 178 465 5.0 79.4177 489 5.48 12.1 179 407 4.71 485.11 180 463 5.02

TABLE 11 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 61 449 5.52 5.9 12 447 5.04 4.8 202 547 6.53 7.3 203 463 6.02 7.1204 467 5.81 24.6 205 474 5.28 223.6 206 479 5.61 5.1 207 450 4.92 19.4208 450 4.53

TABLE 12 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 61 449 5.52 5.9 12 447 5.04 4.8 219 459 5.01 338.5 220 463 5.98511.8 221 451 4.75 1295.1 225 451 4.43 392.3 226 435 5.00 112.9 227 4643.68 231 462 2.6

TABLE 13 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 61 449 5.52 5.9 12 447 5.04 4.8 248 419 4.65 21.1

TABLE 14 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 61 449 5.52 5.9 12 447 5.04 4.8 125 417 5.03 291.4 126 413 4.471298.5 127 467 5.57 44.6 128 426 4.72 5390.50 129 425 3.96 5071.10 130461 3.03 >10000 131 397 4.75 1609.50 245 447 5.49 10.54 132 401 4.472184.70 151 408 3.85 894.3 135 449 5.31 3151.9 136 450 4.58 351.8 134437 4.80 >10000

TABLE 15 PPARd, Compd EC₅₀ (nM) NHR protein interaction assay, No MWClogP (from Salk) EC₅₀ (nM) for PPARδ 57 459 6.14 42 25.9 37 463 6.05 4117.5 61 449 5.52 9 5.9 62 449 5.3 61 36.8 63 465 6.0 ND 8.4 64 465 5.8117.2 8.02 12 447 5.27 19.6 4.8 28 497 6.45 290 18.8 267 469 5.02 19.65.0

TABLE 16 NHR protein interaction assay, Compd No MW ClogP EC₅₀ (nM) forPPARδ 127 467 5.57 44.6 176 421 4.68 12.6 245 447 5.49 10.54 12 447 5.274.8 247 497 6.45 18.8

Example 11 GW Treatment Prevents the Accumulation of VLCFAs by InducingMitochondrial FA Oxidation in a Mouse Model of ALD

As GW treatment dramatically induced mitochondrial fatty acid (FA)oxidation and reduced fat accumulation, GW was evaluated to see if couldimprove FA metabolism disorders such as ALD. ALD is a rare geneticdisorder caused by defects in peroxisomal oxidation of very long-chainfatty acids (VLCFAs), resulting in systemic accumulation of VLCFAs,which causes tissue defects mainly in the central nervous system and theadrenal glands. The majority of VLCFAs in the body are endogenouslysynthesized from long-chain fatty acids (LCFAs). Therefore, onepotential way to prevent VLCFA accumulation in ALD is by inducingmitochondrial LCFA oxidation to reduce the availability of LCFAs forVLCFA biosynthesis. In order to test this, a previously described mousemodel of ALD was used, in which the X-linked adrenoleukodystrophy geneabcd1 was systemically ablated and the knockout (AKO) mice faithfullyrecapitulated the abnormal VLCFA accumulation phenotype seen in ALDpatients.

3-month-old AKO mice were treated with or without GW and their tissuescollected for free FA analysis using GC/MS. Similar to what waspreviously reported, both brain and liver from AKO mice had greatlyincreased levels of VLCFAs including C22:0, C23:0, C24:0, and C26:0,while the levels of total FAs (C12-C26) remained unaffected (FIGS. 10Aand 10B). After 8 weeks of GW treatment, the levels of all four VLCFAsin AKO brain and liver were significantly reduced, with all liver C26:0cleared in most GW-treated animals (FIGS. 10A and 10B). Without beingbound to a particular theory, the reduction of VLCFAs may be due toGW-induced mitochondrial FA oxidation in peripheral tissues, since GWtreatment dramatically induced the expression of mitochondrial FAoxidation genes including Cpt1a and 1b, Slc25a20, and Acadl in AKO liverand skeletal muscle (FIGS. 11A and 11B), which was further supported bythe fact that most saturated LCFAs including C12:0 to C22:0 and thetotal FAs were significantly reduced by GW treatment in both liver andmuscle (FIGS. 12A, 12B and 10B).

While the disclosure has been described and illustrated with referenceto certain embodiments thereof, those having ordinary skill in the artwill appreciate that various changes, modifications, and substitutionscan be made therein without departing from the spirit and scope of thepresent disclosure. For example, effective dosages other than thedosages as set forth herein may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forPPARδ-related disease(s). Likewise, the specific pharmacologicalresponses observed may vary according to and depending on the particularactive compound selected or whether there are present pharmaceuticalcarriers, as well as the type of formulation and mode of administrationemployed, and such expected variations or differences in the results arecontemplated in accordance with the objects and practices of the presentdisclosure. Accordingly, the disclosure is not to be limited as by theappended claims.

The features disclosed in this description and/or in the claims may bothseparately and in any combination thereof be material for realizing thedisclosure in diverse forms thereof.

In view of the many possible embodiments to which the principles of thedisclosure may be applied, it should be recognized that the illustratedembodiments are only examples of the invention and should not be takenas limiting the scope of the invention. Rather, the scope of thedisclosure is defined by the following claims. We therefore claim as ourinvention all that comes within the scope and spirit of these claims.

We claim:
 1. A compound having a formula

wherein: ring A is selected from a cycloalkylene, heterocycloalkylene,arylene or heteroarylene; ring B is selected from an aryl, heteroaryl,cycloalkyl, heterocycloalkyl, cycloalkylene, heterocycloalkylene,arylene or heteroarylene; each R² independently is selected fromdeuterium, halogen, aryl, heteroaryl, aliphatic, heteroaliphatic,cycloaliphatic, NO₂, OH, amino, amide, aminosulfonyl, carboxyl, carboxylester, alkylsulfonyl, SO₃H, or acyl; each R²² independently is selectedfrom deuterium, halogen, aryl, heteroaryl, aliphatic, heteroaliphatic,cycloaliphatic, NO₂, OH, amino, amide, aminosulfonyl, carboxyl, carboxylester, alkylsulfonyl, SO₃H, or acyl; n is from 0 to 5; m is from 0 to 4;X is O, NR³⁰, sulfonyl, or S; R³⁰ is selected from H or aliphatic, aryl,or cycloaliphatic; L⁵ is selected from a bond, aliphatic,heteroaliphatic, arylene, heteroarylene, cycloalkylene,heterocycloalkylene or -L³N(L⁴R³)L³-; L² is selected from a bond,aliphatic, heteroaliphatic, arylene, heteroarylene, cycloalkylene,heterocycloalkylene or —CR²³R²⁴—; R²³ and R²⁴ are each independentlyselected from H, deuterium, halogen, aliphatic, alkyl, —C(O)OR²⁵ or—C(O)NR²⁵R²⁶; R²⁵ and R²⁶ are each independently hydrogen, aliphatic oralkyl; Z is selected from R′L¹C(O)— or a carboxyl bioisostere; L¹ is abond or —NR³⁰—; R¹ is hydrogen, aliphatic, —OR^(1A), —NR^(1A)R^(1B),—C(O)R^(1A), —S(O)₂R^(1A), —C(O)OR^(1A), —S(O)₂NR^(1A)R^(1B) or—C(O)NR^(1A)R^(1B); R^(1A), R^(1B) are each independently hydrogen,aliphatic or alkyl; L³ is selected from a bond, aliphatic, —C(O)—,alkylC(O)—, —C(O)alkyl-, or sulfonyl; L⁴ is selected from a bond,aliphatic, heteroaliphatic, arylene, heteroarylene, cycloalkylene,heterocycloalkylene or —CR²³R²⁴—; R³ is selected from —OH, —OR^(3A),—NR^(3A)R^(3B), —C(O)R^(3A), —S(O)₂R^(3A), —C(O)OR^(3A)S(O)₂NR^(3A)R^(3B), —C(O)NR^(3A)R^(3B), aliphatic, heteroaliphatic,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or R³ can be joined withan atom of ring B to form a fused ring system or may be joined with anatom of L³ to form a heterocyclic ring system; R^(3A), R^(3B), are eachindependently hydrogen, aliphatic or alkyl; with the provisos that if L⁵is —CH₂N(L⁴R³)C(O)—, L⁴R³ is n-propyl or isopropyl, ring A is phenyl,and n is 1 then R² is not 4-bromo or 4-benzo[d][1,3]dioxole; if L⁵ is—CH₂CH₂N(L⁴R³)C(O)NH—, X is S, and L⁴R³ is an unbranched aliphatic oralkyl chain, then L⁴R³ is a C₁-C₆ unbranched aliphatic or alkyl chain;if L⁵ is —CH₂CH₂N(L⁴R³)C(O)NH—, X is S, and L⁴ is an unbranchedaliphatic or alkyl chain, then R³ is not a cyclohexyl; if L⁵ is—CH₂N(L⁴R³)C(O)—, L⁴R³ is isopropyl, ring A and ring B are both phenyl,and n is 1 then the —XL²Z moiety is ortho or para to L⁵, or L⁵ forms afused ring with ring A; and with the provisos that the compound is notselected from4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}aceticacid;{4-[({2-[3-Fluoro-4-(Trifluoromethyl)phenyl]-4-Methyl-1,3-Thiazol-5-Yl}methyl)sulfanyl]-2-Methylphenoxy}aceticacid;2-((4-(2-(3-(2,4-difluorophenyl)-1-heptylureido)ethyl)phenyl)thio)-2-methylpropanoicacid;2-((4-(2-(3-cyclohexyl-1-(4-cyclohexylbutyl)ureido)ethyl)phenyl)thio)-2-methylpropanoicacid;(S)-2-((2-(methoxycarbonyl)phenyl)amino)-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoicacid;2-((4-(2-(1-(4-cyclohexylbutyl)-3-(4-methoxyphenyl)ureido)ethyl)phenyl)thio)-2-methylpropanoicacid;2-((4-(2-(1-(4-cyclohexylbutyl)-3-(3-methoxyphenyl)ureido)ethyl)phenyl)thio)-2-methylpropanoicacid; ethyl 6-(2-((4-bromo-N-propylbenzamido)methyl)phenoxy)hexanoate;ethyl 6-(4-((4-bromo-N-propylbenzamido)methyl)phenoxy)hexanoate; ethyl6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoate;ethyl6-(4-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoate;6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoicacid;6-(4-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoicacid; ethyl6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate;ethyl6-(4-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate;6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid; or6-(4-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid.
 2. The compound of claim 1, wherein ring B is selected fromphenyl, pyridine, thiophene, thiazole, pyrazole, oxazole, isoxazole,benzo[b]furan, indazole, piperidine, cyclohexane, piperidin-2-one,piperazine-2,5-dione or quinazolin-4(3H)-one.
 3. The compound of claim1, wherein the carboxyl bioisostere is selected from

and X⁷, Y⁷, and Z⁷ are each independently selected from N, CH₂ or CO; X⁸is selected from O, S or NMe; and X⁹ is selected from O, N, NH, S, CH orCH₂.
 4. The compound of claim 1, wherein the compound has a formula


5. The compound of claim 1, wherein the compound has a formula selectedfrom:

where Z¹ is selected from carbon, oxygen, sulfur, or NR³⁰, and each Yindependently is selected from carbon or nitrogen;

where Z¹ is selected from carbon, oxygen, sulfur, or NR³⁰, and each Yindependently is selected from carbon or nitrogen;

where X² is selected from a bond, carbon, oxygen, sulfur, or NR³⁰;

where each X³ independently is selected from nitrogen, carbon, NR³⁰, oroxo, and each Y independently is selected from carbon or NR³⁰;

where X¹ is selected from carbon, nitrogen, or N-oxide;

where X¹ is selected from carbon, nitrogen, or N-oxide and X² isselected from a bond, carbon, oxygen, sulfur, or NR³⁰;

where X¹ is selected from carbon, nitrogen, or N-oxide, each Yindependently is selected from carbon or nitrogen, and Z¹ is selectedfrom carbon, oxygen, or sulfur;

where X¹ is selected from carbon, nitrogen, or N-oxide, each Yindependently is selected from carbon or nitrogen, and Z¹ is selectedfrom carbon, oxygen, or sulfur;

each Y independently is selected from carbon or nitrogen, and Z¹ isselected from carbon, oxygen, or sulfur;

where X² is selected from a bond, carbon, oxygen, sulfur, or NR³⁰, Yindependently is selected from carbon or nitrogen, and Z¹ is selectedfrom carbon, oxygen, or sulfur;

where X¹ is selected from carbon, nitrogen, or N-oxide, each X³independently is selected from nitrogen, carbon, NR³⁰, or oxo, and eachY independently is selected from carbon or nitrogen;

where each X³ independently is selected from nitrogen, carbon, NR³⁰, oroxo, each Y independently is selected from carbon or nitrogen, and Z¹ isselected from carbon, oxygen, or sulfur;

where X² is selected from a bond, carbon, oxygen, or sulfur, each X³independently is selected from nitrogen, carbon, NR³⁰, or oxo, and eachY independently is selected from carbon or nitrogen;


6. The compound of claim 1, wherein: R³ is selected from aliphatic oralkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;and/or L², L³ and L⁴ are each independently selected from a bond oralkylene.
 7. The compound of claim 1, wherein L⁴R³ is isopropyl.
 8. Thecompound of claim 1, wherein R² is furan-2-yl or furan-3-yl.
 9. Thecompound of claim 1, wherein L² is selected from


10. The compound of claim 1, wherein: R²² is selected from Br, F,methyl, trifluoromethyl, cyano, methoxy, cyclopropyl or azetidine; n isfrom 2 to 4, and two adjacent R² groups form a fused ring system withring B; and/or R² is selected from bromo, fluoro, methyl,trifluoromethyl, methoxy, trifluoromethoxy, dimethylamino, acetyl,methanesulfonyl, cyano, cyclopropoxy, phenyl, furan-2-yl, furan-3-yl,thiophen-2-yl, thiophen-3-yl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-n-butylphenyl, 4-n-propylphenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl,2-ethylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl,3,5-dimethylphenyl, 3-pyridyl, 4-pyridyl, naphthalen-1-yl,naphthalen-2-yl, (1,1′-biphenyl)-2-yl, pyrrolidin-1-yl,3-(furan-3-yl)phenyl,


11. The compound of claim 1, wherein the compound is selected from6-(2-((N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid; ethyl6-(2-(1-(4-bromo-N-cyclopropylbenzamido)-2-(tert-butylamino)-2-oxoethyl)phenoxy)hexanoate;ethyl6-(2-(2-(tert-butylamino)-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoate;ethyl6-(2-(2-amino-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoate;6-(2-(2-amino-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoicacid;6-(2-(2-(tert-butylamino)-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;N-(2-amino-1-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)-2-oxoethyl)-N-cyclopropyl-[1,1′-biphenyl]-4-carboxamide;6-(2-((N-cyclopropyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-benzyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-benzyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-benzyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-benzyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-benzyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-benzyl-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-benzyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-benzyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoicacid;N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(pyridin-4-yl)benzamide;N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-[1,1′-biphenyl]-4-carboxamide;N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(pyridin-3-yl)benzamide;N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(1H-pyrazol-4-yl)benzamide;N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(thiophen-2-yl)benzamide;N-benzyl-4-(furan-2-yl)-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)benzamide;N-benzyl-4-(furan-3-yl)-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)benzamide;6-(2-((N-(sec-butyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(thiophen-3-yl)benzamide;6-(2-((N-(sec-butyl)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(sec-butyl)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(sec-butyl)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(sec-butyl)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(sec-butyl)-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(sec-butyl)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(sec-butyl)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((4-bromo-N-(sec-butyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(3-morpholinopropyl)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(3-morpholinopropyl)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(3-morpholinopropyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(3-morpholinopropyl)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-3-yl)-N-(3-morpholinopropyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(3-morpholinopropyl)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-2-yl)-N-(3-morpholinopropyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(2-(pyridin-2-yl)ethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(3-morpholinopropyl)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(3-morpholinopropyl)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(1H-pyrazol-4-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-3-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-2-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((4-(furan-3-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopentyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopentyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopentyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopentyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopentyl-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopentyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopentyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(naphthalen-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(naphthalen-1-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-3′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-3′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-3′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4′-ethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′,3′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′-ethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′,5′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′,6′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-3′,5′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-[1,1′:2′,1″-terphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4′-propyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((4′-butyl-N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-sec-butyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-isopropylbiphenyl-4-ylcarboxamido)methyl)phenoxy)hexanoicacid; 6-(2-(2-(4-(furan-2-yl)phenyl)thiazol-5-yl)phenoxy)hexanoic acid;6-(2-(cyclopropyl(4-(furan-2-yl)benzyl)carbamoyl)phenoxy)hexanoic acid;6-(2-((N-cyclopropyl-2-oxoindoline-5-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2-oxo-2,3-dihydrobenzofuran-5-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropylbenzo[c][1,2,5]oxadiazole-5-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-5-(furan-2-yl)thiazole-2-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-[2,3′-bifuran]-5′-carboxamido)methyl)phenoxy)hexanoicacid;6-((4-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)thiophen-3-yl)oxy)hexanoicacid;N-(2-((5-(1H-tetrazol-5-yl)pentyl)oxy)benzyl)-N-cyclopropyl-4-(furan-2-yl)benzamide;6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-3-ynoicacid;6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-4-ynoicacid;(Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-3-enoicacid;(E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-4-enoicacid;(E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-2-enoicacid;(Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-4-enoicacid;(Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-2-enoicacid;(E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-3-enoicacid;6-(2-((N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid; ethyl6-(2-(1-(4-bromo-N-cyclopropylbenzamido)-2-(tert-butylamino)-2-oxoethyl)phenoxy)hexanoate;ethyl6-(2-(2-(tert-butylamino)-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoate;ethyl6-(2-(2-amino-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoate;6-(2-(2-amino-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoicacid;6-(2-(2-(tert-butylamino)-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;N-(2-amino-1-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)-2-oxoethyl)-N-cyclopropyl-[1,1′-biphenyl]-4-carboxamide;6-(2-((N-cyclopropyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-benzyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-benzyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-benzyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-benzyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-benzyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-benzyl-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-benzyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-benzyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoicacid;N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(pyridin-4-yl)benzamide;N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-[1,1′-biphenyl]-4-carboxamide;N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(pyridin-3-yl)benzamide;N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(1H-pyrazol-4-yl)benzamide;N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(thiophen-2-yl)benzamide;N-benzyl-4-(furan-2-yl)-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)benzamide;N-benzyl-4-(furan-3-yl)-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)benzamide;6-(2-((N-(sec-butyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(thiophen-3-yl)benzamide;6-(2-((N-(sec-butyl)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(sec-butyl)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(sec-butyl)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(sec-butyl)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(sec-butyl)-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(sec-butyl)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(sec-butyl)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((4-bromo-N-(sec-butyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(3-morpholinopropyl)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(3-morpholinopropyl)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(3-morpholinopropyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(3-morpholinopropyl)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-3-yl)-N-(3-morpholinopropyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(3-morpholinopropyl)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-2-yl)-N-(3-morpholinopropyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(2-(pyridin-2-yl)ethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(3-morpholinopropyl)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(3-morpholinopropyl)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(1H-pyrazol-4-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-3-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-2-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((4-(furan-3-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopentyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopentyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopentyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopentyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopentyl-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopentyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopentyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(naphthalen-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4-(naphthalen-1-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-3′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-3′-methoxy-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4′-methyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-3′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4′-fluoro-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4′-ethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′,3′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′-ethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′,5′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′,6′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-3′,5′-dimethyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-[1,1′:2′,1″-terphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropyl-4′-propyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((4′-butyl-N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-sec-butyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-isopropylbiphenyl-4-ylcarboxamido)methyl)phenoxy)hexanoicacid; 6-(2-(2-(4-(furan-2-yl)phenyl)thiazol-5-yl)phenoxy)hexanoic acid;6-(2-(cyclopropyl(4-(furan-2-yl)benzyl)carbamoyl)phenoxy)hexanoic acid;6-(2-((N-cyclopropyl-2-oxoindoline-5-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-cyclopropylbenzo[c][1,2,5]oxadiazole-5-carboxamido)methyl)phenoxy)hexanoicacid;6-((4-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)thiophen-3-yl)oxy)hexanoicacid;N-(2-((5-(1H-tetrazol-5-yl)pentyl)oxy)benzyl)-N-cyclopropyl-4-(furan-2-yl)benzamide;6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-3-ynoicacid;6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-4-ynoicacid;(Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-3-enoicacid;(E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-4-enoicacid;(E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-2-enoicacid;(Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-4-enoicacid;(Z)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-2-enoicacid;(E)-6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hex-3-enoicacid;N-cyclopropyl-N-(2-((5-(2,4-dioxothiazolidin-5-yl)pentyl)oxy)benzyl)-4-(furan-2-yl)benzamide;N-cyclopropyl-N-(2-((5-(2,4-dioxooxazolidin-5-yl)pentyl)oxy)benzyl)-4-(furan-2-yl)benzamide;N-cyclopropyl-4-(furan-2-yl)-N-(2-((5-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)pentyl)oxy)benzyl)benzamide;N-cyclopropyl-4-(furan-2-yl)-N-(2-((5-(3-hydroxyisothiazol-5-yl)pentyl)oxy)benzyl)benzamide;N-cyclopropyl-4-(furan-2-yl)-N-(2-((5-(3-hydroxyisoxazol-5-yl)pentyl)oxy)benzyl)benzamide;N-cyclopropyl-N-(2-((5-(2,5-dioxo-2,5-dihydro-1H-imidazol-4-yl)pentyl)oxy)benzyl)-4-(furan-2-yl)benzamide;N-cyclopropyl-N-(2-((5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)pentyl)oxy)benzyl)-4-(furan-2-yl)benzamide;N-cyclopropyl-4-(furan-2-yl)-N-(2-((5-(6-hydroxy-4-oxo-4H-1,3-dioxin-2-yl)pentyl)oxy)benzyl)benzamide;6-(2-((4-cyclopropoxy-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid;6-(2-((N-isopropyl-4-methylbenzamido)methyl)phenoxy)hexanoic acid;6-(2-((4-(cyclopentylethynyl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-((1-methylazetidin-3-yl)ethynyl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((4-chloro-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid;6-(2-((N-isopropyl-4-methoxybenzamido)methyl)phenoxy)hexanoic acid;6-(2-((4-(dimethylamino)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(trifluoromethoxy)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((4-acetyl-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid;6-(2-((N-isopropyl-4-(methylsulfonyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((3′-(furan-3-yl)-N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid; 6-(2-((4-fluoro-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid;6-(2-((N-isopropyl-4-(4-methoxytetrahydro-2H-pyran-4-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(3,3,3-trifluoroprop-1-yn-1-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(oxetan-3-ylethynyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(cyclobutylethynyl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(1-(trifluoromethyl)cyclopropyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(1-methoxycyclopropyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(tetrahydro-2H-pyran-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(4-methylbicyclo[2.2.2]octan-1-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(6-oxo-1,6-dihydropyridin-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(oxetan-2-ylethynyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(4-(trifluoromethyl)bicyclo[2.2.2]octan-1-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(4-phenylbicyclo[2.2.2]octan-1-yl)benzamido)methyl)phenoxy)hexanoicacid 6-(2-((4-cyano-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid;6-(2-((N-isopropyl-4-(oxetan-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(pyrrolidin-1-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((5-(furan-2-yl)-N-isopropylpicolinamido)methyl)phenoxy)hexanoicacid;6-(2-((2-(furan-2-yl)-N-isopropylthiazole-5-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-2-yl)-N-isopropyl-2,5-dioxopiperazine-1-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-(((4-(furan-2-yl)-N-isopropylphenyl)sulfonamido)methyl)phenoxy)hexanoicacid;6-(2-(2-((4-(furan-2-yl)phenyl)(isopropyl)amino)-2-oxoethyl)phenoxy)hexanoicacid;6-(2-((6-(furan-2-yl)-N-isopropylnicotinamido)methyl)phenoxy)hexanoicacid; 6-(2-((4-(furan-2-yl)benzyl)(isopropyl)carbamoyl)phenoxy)hexanoicacid;6-(2-((2-(furan-2-yl)-N-isopropyloxazole-5-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-(3-((4-(furan-2-yl)phenyl)(isopropyl)amino)-3-oxopropyl)phenoxy)hexanoicacid;6-(2-((2-fluoro-4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((3-fluoro-4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((1-(furan-2-yl)-N-isopropylpiperidine-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((5-(furan-2-yl)-N-isopropylisoxazole-3-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-2-yl)-N-isopropylcyclohexane-1-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-(((6-(furan-2-yl)-1H-indazol-3-yl)(isopropyl)amino)methyl)phenoxy)hexanoicacid;6-(2-((5-(furan-2-yl)-N-isopropylthiazole-2-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-2-methylbenzofuran-6-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-2-methylbenzofuran-5-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((7-(furan-2-yl)-4-oxoquinazolin-3(4H)-yl)methyl)phenoxy)hexanoicacid;6-(2-((1-(furan-2-yl)-N-isopropyl-2-oxopiperidine-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((5-(furan-2-yl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((5-(furan-2-yl)-N-isopropyl-1-methyl-1H-pyrazole-3-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((5-(furan-2-yl)-N-isopropyl-3,6-dioxopiperazine-2-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-2-yl)-N-isopropylpiperidine-1-carboxamido)methyl)phenoxy)hexanoicacid; 6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-2-yl)-N-(2,2,2-trifluoroethyl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-2-yl)-N-(2-methoxyethyl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic acid;6-(2-((4-(furan-2-yl)-N-(oxetan-3-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((2-(4-(furan-2-yl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid;6-(2-((N-(2-cyanopropan-2-yl)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((2-(4-(furan-2-yl)phenyl)-4-methyl-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid;6-(2-(2-(4-(furan-2-yl)phenyl)-1-methyl-1H-imidazol-5-yl)phenoxy)hexanoicacid;6-(2-((6-(furan-2-yl)-3-methyl-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenoxy)hexanoicacid; 6-(2-((4-(furan-2-yl)-N-hydroxybenzamido)methyl)phenoxy)hexanoicacid;6-(2-((3-(4-(furan-2-yl)phenyl)-5-methylisoxazol-4-yl)methyl)phenoxy)hexanoicacid; 6-(2-((4-(furan-2-yl)-N-methoxybenzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(cyclopropylmethyl)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(1-cyclopropylethyl)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-(1-(4-(furan-2-yl)benzoyl)pyrrolidin-2-yl)phenoxy)hexanoicacid; 6-(2-(1-(4-(furan-2-yl)benzoyl)azetidin-2-yl)phenoxy)hexanoicacid; 6-(2-(1-(4-(furan-2-yl)benzoyl)piperidin-2-yl)phenoxy)hexanoicacid;6-(4-bromo-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)-4-methylphenoxy)hexanoicacid;6-(4-fluoro-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(4-cyano-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)-4-methoxyphenoxy)hexanoicacid;6-((3-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-2-yl)oxy)hexanoicacid;6-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-3-yl)oxy)hexanoicacid;6-((3-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-4-yl)oxy)hexanoicacid;6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)-1-methyl-1H-pyrazol-3-yl)oxy)hexanoicacid;6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyridin-3-yl)oxy)hexanoicacid;6-((2-(4-(furan-2-yl)benzoyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)hexanoicacid;6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)isothiazol-3-yl)oxy)hexanoicacid;6-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)cyclopentyl)oxy)hexanoicacid;6-(4-cyclopropyl-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)cyclohexyl)oxy)hexanoicacid;6-(4-(azetidin-1-yl)-2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)-4-(trifluoromethyl)phenoxy)hexanoicacid;N-(2-(4-(2H-tetrazol-5-yl)butoxy)benzyl)-4-(furan-2-yl)-N-isopropylbenzamide;7-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)heptanoicacid;2-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)propoxy)aceticacid;5-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethyl)isoxazole-3-carboxylicacid;2-(5-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)methyl)isoxazol-3-yl)aceticacid;2-(4-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)cyclohexyl)aceticacid;5-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)pentanoicacid;3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethoxy)propanoicacid;3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)acetamido)propanoicacid;3-(4-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)methyl)thiazol-2-yl)propanoicacid;3-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethyl)cyclobutane-1-carboxylicacid;3-((2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethyl)amino)-3-oxopropanoicacid;3-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)azetidin-1-yl)propanoicacid;6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)heptanoicacid;2-(3-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)methyl)azetidin-1-yl)aceticacid;2-(4-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)methyl)thiazol-2-yl)aceticacid;2-((3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)propyl)thio)aceticacid;2-((3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)cyclopentyl)oxy)aceticacid;1-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)acetyl)pyrrolidine-3-carboxylicacid;1-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethyl)pyrrolidine-3-carboxylicacid;(E)-6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)-4-methylhex-4-enoicacid;(S)-4-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenyl)sulfonyl)-2,3-dihydro-1H-indene-2-carboxylicacid;4-(furan-2-yl)-N-(2-(4-(5-hydroxy-1,3,4-oxadiazol-2-yl)butoxy)benzyl)-N-isopropylbenzamide;1-(2-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)ethyl)azetidine-3-carboxylicacid;2-(4-((2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)aceticacid;3-(3-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)piperidin-1-yl)propanoicacid;6-(2-((4-(cyclopropylethynyl)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-(1-(4-(furan-2-yl)benzyl)-5-methyl-1H-imidazol-2-yl)phenoxy)hexanoicacid;6-(2-((4-(4-(furan-2-yl)phenyl)-5-methylisoxazol-3-yl)methyl)phenoxy)hexanoicacid; 6-(2-((N-benzyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(cyclopropylethynyl)-N-methylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-methyl-4-(3,3,3-trifluoroprop-1-yn-1-yl)benzamido)methyl)phenoxy)hexanoicacid; 6-(2-((4-cyclopropoxy-N-methylbenzamido)methyl)phenoxy)hexanoicacid; 6-(2-((5-(furan-2-yl)-N-methylpicolinamido)methyl)phenoxy)hexanoicacid;6-(2-((5-(furan-2-yl)-N-methylthiazole-2-carboxamido)methyl)phenoxy)hexanoicacid;3-(2-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)ethoxy)propanoicacid;N-(2-(4-(2H-tetrazol-5-yl)butoxy)benzyl)-4-(furan-2-yl)-N-methylbenzamide;6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)heptanoic acid;6-((3-((4-(furan-2-yl)-N-methylbenzamido)methyl)pyridin-2-yl)oxy)hexanoicacid;6-((3-((6-(furan-2-yl)-N-methylnicotinamido)methyl)pyridin-2-yl)oxy)hexanoicacid;6-(4-fluoro-2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)-4-methoxyphenoxy)hexanoicacid;6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)-4-methylphenoxy)hexanoicacid;6-(2-((6-(cyclopropylethynyl)-N-isopropylnicotinamido)methyl)phenoxy)hexanoicacid;6-(2-((6-(cyclopropylethynyl)-N-methylnicotinamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(but-2-yn-1-yl)-6-(furan-2-yl)nicotinamido)methyl)phenoxy)hexanoicacid; 6-(2-((6-fluoro-N-isopropylnicotinamido)methyl)phenoxy)hexanoicacid;6-(2-((6-fluoro-N-(furan-2-ylmethyl)nicotinamido)methyl)phenoxy)hexanoicacid; 6-(2-((N-benzyl-6-fluoronicotinamido)methyl)phenoxy)hexanoic acid;6-(2-(2-(4-(furan-2-yl)phenyl)pyrrolidine-1-carbonyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((N-(sec-butyl)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoicacid;6-(2-((N-isopropyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoicacid; sodium6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoate;2-(2-methyl-4-(((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methyl)thio)phenoxy)aceticacid;(E)-6-(2-((4-(furan-2-yl)-N′-hydroxy-N-isopropylbenzimidamido)methyl)phenoxy)hexanoicacid;6-(2-((4-((fluoromethyl)thio)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-((difluoromethyl)thio)-N-isopropylbenzamido)methyl)phenoxy)hexanoicacid;6-(2-((4-fluoro-5-(furan-2-yl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl)phenoxy)hexanoicacid;6-(2-((5-(cyclopropylethynyl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl)phenoxy)hexanoicacid;(R)-6-(2-((5-(furan-2-yl)-N-isopropyl-1H-pyrazole-3-carboxamido)methyl)phenoxy)heptanoicacid;6-(2-((3-(4-(furan-2-yl)phenyl)-5-methyl-4H-1,2,4-triazol-4-yl)methyl)phenoxy)hexanoicacid;6-(2-((5-(4-(furan-2-yl)phenyl)-3-methyl-1H-1,2,4-triazol-1-yl)methyl)phenoxy)hexanoicacid;6-(2-((2-(5-(furan-2-yl)pyridin-2-yl)-4-methyl-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid;6-(2-((2-(5-(furan-2-yl)pyridin-2-yl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid;6-(2-((2-(4-(furan-2-yl)phenyl)-5-methyl-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid;6-(2-((2-(4-(furan-2-yl)phenyl)-4-methyl-1H-imidazol-1-yl)methyl)phenoxy)hexanoicacid;6-(2-(5-(4-(furan-2-yl)phenyl)-1-methyl-1H-imidazol-2-yl)phenoxy)hexanoicacid; 6-(2-((4-(furan-2-yl)benzyl)(isopropyl)carbamoyl)phenoxy)hexanoicacid;6-(2-(2-((4-(furan-2-yl)phenyl)(isopropyl)amino)-2-oxoethyl)phenoxy)hexanoicacid;6-(2-(2-(4-(furan-2-yl)phenyl)piperidine-1-carbonyl)phenoxy)hexanoicacid;6-(2-(2-(4-(furan-2-yl)phenyl)azetidine-1-carbonyl)phenoxy)hexanoicacid;6-(2-((3-(4-(furan-2-yl)benzoyl)isoxazol-4-yl)methyl)phenoxy)hexanoicacid;6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)pyrrolidin-3-yl)oxy)hexanoicacid;6-((4-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)morpholin-3-yl)oxy)hexanoicacid; or6-(2-(1-(4-(furan-2-yl)benzyl)-4-methyl-1H-imidazol-2-yl)phenoxy)hexanoicacid;
 12. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of claim
 1. 13. A method, comprisingcontacting a PPARδ protein with an effective amount of one or morecompounds of claim
 1. 14. The method of claim 13, wherein the PPARδprotein is present in a subject, and contacting comprises administeringan effective amount of the one or more compounds or the pharmaceuticalcomposition to the subject, wherein administering comprisesintraarticular, intravenous, intramuscular, intratumoral, intradermal,intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalational,transdermal, or rectal administration.
 15. The method of claim 13,wherein the one or more compounds or the composition are administered tothe subject to provide a dose of at least one compound in atherapeutically effective amount of from about 1 mg/kg to about 10mg/kg.